Surreal-GAN: Semi-Supervised Representation Learning via GAN for uncovering heterogeneous disease-related imaging patterns

A plethora of machine learning methods have been applied to imaging data, enabling the construction of clinically relevant imaging signatures of neurological and neuropsychiatric diseases. Oftentimes, such methods do not explicitly model the heterogeneity of disease effects, or approach it via nonlinear models that are not interpretable. Moreover, unsupervised methods may parse heterogeneity that is driven by nuisance confounding factors that affect global brain structure or function, rather than heterogeneity relevant to a pathology of interest. On the other hand, semi-supervised clustering methods seek to derive a pathology-related dichotomous subtypes, ignoring the truth that disease heterogeneity spatially and temporally extends along a continuum. To address the aforementioned limitations, herein, we propose a novel method, termed Surreal-GAN (Semi-SUpeRvised ReprEsentAtion Learning via GAN). Using cross-sectional imaging data, Surreal-GAN dissects underlying disease-related heterogeneity under the principle of semi-supervised clustering [cluster mappings from the normal control (CN) to patient (PT) domain], proposes a continuously dimensional representation, and infers the disease severity of patients at individual level along each dimension. The model first learns a transformation function from the CN domain to the PT domain with latent variables controlling transformation directions. An inverse mapping function together with regularization on function continuity, pattern orthogonality and monotonicity was also imposed to make sure that the transformation function captures necessarily meaningful imaging patterns with clinical significance. We first validated the model through semi-synthetic experiments, and then demonstrated its potential in capturing biologically plausible imaging patterns in Alzheimer's disease (AD).