Abstract
PURPOSE: Causal deep learning (DL) using normalizing flows allows the generation of true counterfactual images, which is relevant for many medical applications such as explainability of decisions, image harmonization, and in-silico studies. However, such models are computationally expensive when applied directly to high-resolution 3D images and, therefore, require image dimensionality reduction (DR) to efficiently process the data. The goal of this work was to compare how different DR methods affect counterfactual neuroimage generation. APPROACH: Five DR techniques [2D principal component analysis (PCA), 2.5D PCA, 3D PCA, autoencoder, and Vector Quantised-Variational AutoEncoder] were applied to 23,692 3D brain images to create low-dimensional representations for causal DL model training. Convolutional neural networks were used to quantitatively evaluate age and sex changes on the counterfactual neuroimages. Age alterations were measured using the mean absolute error (MAE), whereas sex changes were assessed via classification accuracy. RESULTS: The 2.5D PCA technique achieved the lowest MAE of 4.16 when changing the age variable of an original image. When sex was changed, the autoencoder embedding led to the highest classification accuracy of 97.84% while also significantly impacting the age variable predictions, increasing the MAE to 5.24 years. Overall, 3D PCA provided the best balance, with an age prediction MAE of 4.57 years while maintaining 94.01% sex classification accuracy when altering the age variable and 94.73% sex classification accuracy and the lowest age prediction MAE (3.84 years) when altering the sex variable. CONCLUSIONS: 3D PCA appears to be the best-suited DR method for causal neuroimage analysis.