From Group-Differences to Single-Subject Probability: Conformal Prediction-based Uncertainty Estimation for Brain-Age Modeling

The brain-age gap is one of the most investigated risk markers for brain changes across disorders. While the field is progressing towards large-scale models, recently incorporating uncertainty estimates, no model to date provides the single-subject risk assessment capability essential for clinical application. In order to enable the clinical use of brain-age as a biomarker, we here combine uncertainty-aware deep Neural Networks with conformal prediction theory. This approach provides statistical guarantees with respect to single-subject uncertainty estimates and allows for the calculation of an individual's probability for accelerated brain-aging. Building on this, we show empirically in a sample of N=16,794 participants that 1. a lower or comparable error as state-of-the-art, large-scale brain-age models, 2. the statistical guarantees regarding single-subject uncertainty estimation indeed hold for every participant, and 3. that the higher individual probabilities of accelerated brain-aging derived from our model are associated with Alzheimer's Disease, Bipolar Disorder and Major Depressive Disorder.

An Uncertainty-Aware, Shareable and Transparent Neural Network Architecture for Brain-Age Modeling

The deviation between chronological age and age predicted from neuroimaging data has been identified as a sensitive risk-marker of cross-disorder brain changes, growing into a cornerstone of biological age-research. However, Machine Learning models underlying the field do not consider uncertainty, thereby confounding results with training data density and variability. Also, existing models are commonly based on homogeneous training sets, often not independently validated, and cannot be shared due to data protection issues. Here, we introduce an uncertainty-aware, shareable, and transparent Monte-Carlo Dropout Composite-Quantile-Regression (MCCQR) Neural Network trained on N=10,691 datasets from the German National Cohort. The MCCQR model provides robust, distribution-free uncertainty quantification in high-dimensional neuroimaging data, achieving lower error rates compared to existing models across ten recruitment centers and in three independent validation samples (N=4,004). In two examples, we demonstrate that it prevents spurious associations and increases power to detect accelerated brain-aging. We make the pre-trained model publicly available.

Predicting brain-age from raw T 1 -weighted Magnetic Resonance Imaging data using 3D Convolutional Neural Networks

Age prediction based on Magnetic Resonance Imaging (MRI) data of the brain is a biomarker to quantify the progress of brain diseases and aging. Current approaches rely on preparing the data with multiple preprocessing steps, such as registering voxels to a standardized brain atlas, which yields a significant computational overhead, hampers widespread usage and results in the predicted brain-age to be sensitive to preprocessing parameters. Here we describe a 3D Convolutional Neural Network (CNN) based on the ResNet architecture being trained on raw, non-registered T$_ 1$-weighted MRI data of N=10,691 samples from the German National Cohort and additionally applied and validated in N=2,173 samples from three independent studies using transfer learning. For comparison, state-of-the-art models using preprocessed neuroimaging data are trained and validated on the same samples. The 3D CNN using raw neuroimaging data predicts age with a mean average deviation of 2.84 years, outperforming the state-of-the-art brain-age models using preprocessed data. Since our approach is invariant to preprocessing software and parameter choices, it enables faster, more robust and more accurate brain-age modeling.