Albert Montillo

Alex Treacher, Kevin Nguyen, Dylan Owens et al.

This work demonstrates the ability to produce readily interpretable statistical metrics for model fit, fixed effects covariance coefficients, and prediction confidence. Importantly, this work compares 4 suitable and commonly applied epistemic UQ approaches, BNN, SWAG, MC dropout, and ensemble approaches in their ability to calculate these statistical metrics for the ARMED MEDL models. In our experiment for AD prognosis, not only do the UQ methods provide these benefits, but several UQ methods maintain the high performance of the original ARMED method, some even provide a modest (but not statistically significant) performance improvement. The ensemble models, especially the ensemble method with a 90% subsampling, performed well across all metrics we tested with (1) high performance that was comparable to the non-UQ ARMED model, (2) properly deweights the confounds probes and assigns them statistically insignificant p-values, (3) attains relatively high calibration of the output prediction confidence. Based on the results, the ensemble approaches, especially with a subsampling of 90%, provided the best all-round performance for prediction and uncertainty estimation, and achieved our goals to provide statistical significance for model fit, statistical significance covariate coefficients, and confidence in prediction, while maintaining the baseline performance of MEDL using ARMED

Son Nguyen, Adam Wang, Albert Montillo

Traditional deep learning (DL) models have two ubiquitous limitations. First, they assume training samples are independent and identically distributed (i.i.d), an assumption often violated in real-world datasets where samples have additional correlation due to repeat measurements (e.g., on the same participants in a longitudinal study or cells from the same sequencer). This leads to performance degradation, limited generalization, and covariate confounding, which induces Type I and Type II errors. Second, DL models typically prioritize overall accuracy, favoring accuracy on the majority while sacrificing performance for underrepresented subpopulations, leading to unfair, biased models. This is critical to remediate, particularly in models which influence decisions regarding loan approvals and healthcare. To address these issues, we propose the Fair Mixed Effects Deep Learning (Fair MEDL) framework. This framework quantifies cluster-invariant fixed effects (FE) and cluster-specific random effects (RE) through: 1) a cluster adversary for learning invariant FE, 2) a Bayesian neural network for RE, and 3) a mixing function combining FE and RE for final predictions. Fairness is enhanced through architectural and loss function changes introduced by an adversarial debiasing network. We formally define and demonstrate improved fairness across three metrics: equalized odds, demographic parity, and counterfactual fairness, for both classification and regression tasks. Our method also identifies and de-weights confounded covariates, mitigating Type I and II errors. The framework is comprehensively evaluated across three datasets spanning two industries, including finance and healthcare. The Fair MEDL framework improves fairness by 86.4% for Age, 64.9% for Race, 57.8% for Sex, and 36.2% for Marital status, while maintaining robust predictive performance.

Elodie Germani, Nikhil Baghwat, Mathieu Dugré et al.

Parkinson's disease (PD) is a common neurodegenerative disorder with a poorly understood physiopathology and no established biomarkers for the diagnosis of early stages and for prediction of disease progression. Several neuroimaging biomarkers have been studied recently, but these are susceptible to several sources of variability related for instance to cohort selection or image analysis. In this context, an evaluation of the robustness of such biomarkers to variations in the data processing workflow is essential. This study is part of a larger project investigating the replicability of potential neuroimaging biomarkers of PD. Here, we attempt to reproduce (re-implementing the experiments with the same data, same method) and replicate (different data and/or method) the models described in [1] to predict individual's PD current state and progression using demographic, clinical and neuroimaging features (fALFF and ReHo extracted from resting-state fMRI). We use the Parkinson's Progression Markers Initiative dataset (PPMI, ppmi-info.org), as in [1] and aim to reproduce the original cohort, imaging features and machine learning models as closely as possible using the information available in the paper and the code. We also investigated methodological variations in cohort selection, feature extraction pipelines and sets of input features. Different criteria were used to evaluate the reproduction and compare the reproduced results with the original ones. Notably, we obtained significantly better than chance performance using the analysis pipeline closest to that in the original study (R2 \> 0), which is consistent with its findings. Moreover, using derived data provided by the authors of the original study, we were able to make an exact reproduction and managed to obtain results that were close to the original ones. The challenges encountered while reproducing and replicating the original work are likely explained by the complexity of neuroimaging studies, in particular in clinical settings. We provide recommendations to further facilitate the reproducibility of such studies in the future.

Aixa X. Andrade, Son Nguyen, Austin Marckx et al.

Single-cell RNA sequencing enables high-resolution analysis of cellular heterogeneity, yet disentangling biological signal from batch effects remains a major challenge. Existing batch-correction algorithms suppress or discard batch-related variation rather than modeling it. We propose scMEDAL, single-cell Mixed Effects Deep Autoencoder Learning, a framework that separately models batch-invariant and batch-specific effects using two complementary subnetworks. The principal innovation, scMEDAL-RE, is a random-effects Bayesian autoencoder that learns batch-specific representations while preserving biologically meaningful information confounded with batch effects signal often lost under standard correction. Complementing it, the fixed-effects subnetwork, scMEDAL-FE, trained via adversarial learning provides a default batch-correction component. Evaluations across diverse conditions (autism, leukemia, cardiovascular), cell types, and technical and biological effects show that scMEDAL-RE produces interpretable, batch-specific embeddings that complement both scMEDAL-FE and established correction methods (scVI, Scanorama, Harmony, SAUCIE), yielding more accurate prediction of disease status, donor group, and tissue. scMEDAL also provides generative visualizations, including counterfactual reconstructions of a cell's expression as if acquired in another batch. The framework allows substitution of the fixed-effects component with other correction methods, while retaining scMEDAL-RE's enhanced predictive power and visualization. Overall, scMEDAL is a versatile, interpretable framework that complements existing correction, providing enhanced insight into cellular heterogeneity and data acquisition.

Alex H. Treacher, Albert Montillo

We present two novel hyperparameter optimization strategies for optimization of deep learning models with a modular architecture constructed of multiple subnetworks. As complex networks with multiple subnetworks become more frequently applied in machine learning, hyperparameter optimization methods are required to efficiently optimize their hyperparameters. Existing hyperparameter searches are general, and can be used to optimize such networks, however, by exploiting the multi-subnetwork architecture, these searches can be sped up substantially. The proposed methods offer faster convergence to a better-performing final model. To demonstrate this, we propose 2 independent approaches to enhance these prior algorithms: 1) a divide-and-conquer approach, in which the best subnetworks of top-performing models are combined, allowing for more rapid sampling of the hyperparameter search space. 2) A subnetwork adaptive approach that distributes computational resources based on the importance of each subnetwork, allowing more intelligent resource allocation. These approaches can be flexibily applied to many hyperparameter optimization algorithms. To illustrate this, we combine our approaches with the commonly-used Bayesian optimization method. Our approaches are then tested against both synthetic examples and real-world examples and applied to multiple network types including convolutional neural networks and dense feed forward neural networks. Our approaches show an increased optimization efficiency of up to 23.62x, and a final performance boost of up to 3.5% accuracy for classification and 4.4 MSE for regression, when compared to comparable BO approach.

Kevin P. Nguyen, Albert Montillo

Natural science datasets frequently violate assumptions of independence. Samples may be clustered (e.g. by study site, subject, or experimental batch), leading to spurious associations, poor model fitting, and confounded analyses. While largely unaddressed in deep learning, this problem has been handled in the statistics community through mixed effects models, which separate cluster-invariant fixed effects from cluster-specific random effects. We propose a general-purpose framework for Adversarially-Regularized Mixed Effects Deep learning (ARMED) models through non-intrusive additions to existing neural networks: 1) an adversarial classifier constraining the original model to learn only cluster-invariant features, 2) a random effects subnetwork capturing cluster-specific features, and 3) an approach to apply random effects to clusters unseen during training. We apply ARMED to dense, convolutional, and autoencoder neural networks on 4 applications including simulated nonlinear data, dementia prognosis and diagnosis, and live-cell image analysis. Compared to prior techniques, ARMED models better distinguish confounded from true associations in simulations and learn more biologically plausible features in clinical applications. They can also quantify inter-cluster variance and visualize cluster effects in data. Finally, ARMED improves accuracy on data from clusters seen during training (up to 28% vs. conventional models) and generalization to unseen clusters (up to 9% vs. conventional models).

Cooper J. Mellema, Alex Treacher, Kevin P. Nguyen et al.

Currently, the diagnosis of Autism Spectrum Disorder (ASD) is dependent upon a subjective, time-consuming evaluation of behavioral tests by an expert clinician. Non-invasive functional MRI (fMRI) characterizes brain connectivity and may be used to inform diagnoses and democratize medicine. However, successful construction of deep learning models from fMRI requires addressing key choices about the model's architecture, including the number of layers and number of neurons per layer. Meanwhile, deriving functional connectivity (FC) features from fMRI requires choosing an atlas with an appropriate level of granularity. Once a model has been built, it is vital to determine which features are predictive of ASD and if similar features are learned across atlas granularity levels. To identify aptly suited architectural configurations, probability distributions of the configurations of high versus low performing models are compared. To determine the effect of atlas granularity, connectivity features are derived from atlases with 3 levels of granularity and important features are ranked with permutation feature importance. Results show the highest performing models use between 2-4 hidden layers and 16-64 neurons per layer, granularity dependent. Connectivity features identified as important across all 3 atlas granularity levels include FC to the supplementary motor gyrus and language association cortex, regions associated with deficits in social and sensory processing in ASD. Importantly, the cerebellum, often not included in functional analyses, is also identified as a region whose abnormal connectivity is highly predictive of ASD. Results of this study identify important regions to include in future studies of ASD, help assist in the selection of network architectures, and help identify appropriate levels of granularity to facilitate the development of accurate diagnostic models of ASD.

Vyom Raval, Kevin P. Nguyen, Ashley Gerald et al.

Parkinson's disease (PD) is a common neurological disorder characterized by gait impairment. PD has no cure, and an impediment to developing a treatment is the lack of any accepted method to predict disease progression rate. The primary aim of this study was to develop a model using clinical measures and biomechanical measures of gait and postural stability to predict an individual's PD progression over two years. Data from 160 PD subjects were utilized. Machine learning models, including XGBoost and Feed Forward Neural Networks, were developed using extensive model optimization and cross-validation. The highest performing model was a neural network that used a group of clinical measures, achieved a PPV of 71% in identifying fast progressors, and explained a large portion (37%) of the variance in an individual's progression rate on held-out test data. This demonstrates the potential to predict individual PD progression rate and enrich trials by analyzing clinical and biomechanical measures with machine learning.

Kevin P. Nguyen, Cherise Chin Fatt, Alex Treacher et al.

The application of deep learning to build accurate predictive models from functional neuroimaging data is often hindered by limited dataset sizes. Though data augmentation can help mitigate such training obstacles, most data augmentation methods have been developed for natural images as in computer vision tasks such as CIFAR, not for medical images. This work helps to fills in this gap by proposing a method for generating new functional Magnetic Resonance Images (fMRI) with realistic brain morphology. This method is tested on a challenging task of predicting antidepressant treatment response from pre-treatment task-based fMRI and demonstrates a 26% improvement in performance in predicting response using augmented images. This improvement compares favorably to state-of-the-art augmentation methods for natural images. Through an ablative test, augmentation is also shown to substantively improve performance when applied before hyperparameter optimization. These results suggest the optimal order of operations and support the role of data augmentation method for improving predictive performance in tasks using fMRI.