Genetic Architectures of Medical Images Revealed by Registration of Multiple Modalities

The advent of biobanks with vast quantities of medical imaging and paired genetic measurements creates huge opportunities for a new generation of genotype-phenotype association studies. However, disentangling biological signals from the many sources of bias and artifacts remains difficult. Using diverse medical images and time-series (ie, magnetic resonance imagings [MRIs], electrocardiograms [ECGs], and dual-energy X-ray absorptiometries [DXAs]), we show how registration, both spatial and temporal, guided by domain knowledge or learned de novo, helps uncover biological information. A multimodal autoencoder comparison framework quantifies and characterizes how registration affects the representations that unsupervised and self-supervised encoders learn. In this study we (1) train autoencoders before and after registration with nine diverse types of medical image, (2) demonstrate how neural network-based methods (VoxelMorph, DeepCycle, and DropFuse) can effectively learn registrations allowing for more flexible and efficient processing than is possible with hand-crafted registration techniques, and (3) conduct exhaustive phenotypic screening, comprised of millions of statistical tests, to quantify how registration affects the generalizability of learned representations. Genome- and phenome-wide association studies (GWAS and PheWAS) uncover significantly more associations with registered modality representations than with equivalently trained and sized representations learned from native coordinate spaces. Specifically, registered PheWAS yielded 61 more disease associations for ECGs, 53 more disease associations for cardiac MRIs, and 10 more disease associations for brain MRIs. Registration also yields significant increases in the coefficient of determination when regressing continuous phenotypes (eg, 0.36 ± 0.01 with ECGs and 0.11 ± 0.02 for DXA scans). Our findings reveal the crucial role registration plays in enhancing the characterization of physiological states across a broad range of medical imaging data types. Importantly, this finding extends to more flexible types of registration, such as the cross-modal and the circular mapping methods presented here.