Modeling multi-stage disease progression and identifying genetic risk factors via a novel collaborative learning method.

Motivation: Alzheimer's disease (AD) typically progresses gradually for ages rather than suddenly. Thus, staging AD progression in different phases could aid in accurate diagnosis and treatment. In addition, identifying genetic variations that influence AD is critical to understanding the pathogenesis. However, staging the disease progression and identifying genetic variations are usually handled separately.

Results: To address this limitation, we propose a novel sparse multi-stage multi-task mixed-effects collaborative longitudinal regression method (MSColoR). Our method jointly models long disease progression as a multi-stage procedure and identifies genetic risk factors underpinning this complex trajectory. Specifically, MSColoR models multi-stage disease progression using longitudinal neuroimaging-derived phenotypes, and associates the fitted disease trajectories with genetic variations at each stage. Furthermore, we collaboratively leverage summary statistics from large GWAS to improve the powers. Finally, an efficient optimization algorithm is introduced to solve MSColoR. We evaluate our method using both synthetic and real longitudinal neuroimaging and genetic data. Both results demonstrate that MSColoR can reduce modeling errors while identifying more accurate and significant genetic variations compared to other longitudinal methods. Consequently, MSColoR holds great potential as a computational technique for longitudinal brain imaging genetics and AD studies.

Availability: The code is publicly available at https://github.com/dulei323/MSColoR.

Supplementary Information: Supplementary data are available at Bioinformatics online.