Improving genetic risk prediction across diverse population by disentangling ancestry representations.

Risk prediction models using genetic data have seen increasing traction in genomics. However, most of the polygenic risk models were developed using data from participants with similar (mostly European) ancestry. This can lead to biases in the risk predictors resulting in poor generalization when applied to minority populations and admixed individuals such as African Americans. To address this issue, largely due to the prediction models being biased by the underlying population structure, we propose a deep-learning framework that leverages data from diverse population and disentangles ancestry from the phenotype-relevant information in its representation. The ancestry disentangled representation can be used to build risk predictors that perform better across minority populations. We applied the proposed method to the analysis of Alzheimer's disease genetics. Comparing with standard linear and nonlinear risk prediction methods, the proposed method substantially improves risk prediction in minority populations, including admixed individuals, without needing self-reported ancestry information.

GhostKnockoff inference empowers identification of putative causal variants in genome-wide association studies.

Recent advances in genome sequencing and imputation technologies provide an exciting opportunity to comprehensively study the contribution of genetic variants to complex phenotypes. However, our ability to translate genetic discoveries into mechanistic insights remains limited at this point. In this paper, we propose an efficient knockoff-based method, GhostKnockoff, for genome-wide association studies (GWAS) that leads to improved power and ability to prioritize putative causal variants relative to conventional GWAS approaches. The method requires only Z-scores from conventional GWAS and hence can be easily applied to enhance existing and future studies. The method can also be applied to meta-analysis of multiple GWAS allowing for arbitrary sample overlap. We demonstrate its performance using empirical simulations and two applications: (1) a meta-analysis for Alzheimer's disease comprising nine overlapping large-scale GWAS, whole-exome and whole-genome sequencing studies and (2) analysis of 1403 binary phenotypes from the UK Biobank data in 408,961 samples of European ancestry. Our results demonstrate that GhostKnockoff can identify putatively functional variants with weaker statistical effects that are missed by conventional association tests.

Learning to Disentangle Inter-Subject Anatomical Variations in Electrocardiographic Data.

OBJECTIVE: This work investigates the possibility of disentangled representation learning of inter-subject anatomical variations within electrocardiographic (ECG) data. METHODS: Since ground truth anatomical factors are generally not known in clinical ECG for assessing the disentangling ability of the models, the presented work first proposes the SimECG data set, a 12-lead ECG data set procedurally generated with a controlled set of anatomical generative factors. Second, to perform such disentanglement, the presented method evaluates and compares deep generative models with latent density modeled by nonparametric Indian Buffet Process to account for the complex generative process of ECG data. RESULTS: In the simulated data, the experiments demonstrate, for the first time, concrete evidence of the possibility to disentangle key generative anatomical factors within ECG data in separation from task-relevant generative factors. We achieve a disentanglement score of 92.1% while disentangling five anatomical generative factors and the task-relevant generative factor. In both simulated and real-data experiments, this work further provides quantitative evidence for the benefit of disentanglement learning on the downstream clinical task of localizing the origin of ventricular activation. Overall, the presented method achieves an improvement of around 18.5%, and 11.3% for the simulated dataset, and around 7.2%, and 3.6% for the real dataset, over baseline CNN, and standard generative model, respectively. CONCLUSION: These results demonstrate the importance as well as the feasibility of the disentangled representation learning of inter-subject anatomical variations within ECG data. SIGNIFICANCE: This work suggests the important research direction to deal with the well-known challenge posed by the presence of significant inter-subject variations during an automated analysis of ECG data.

A hybrid machine learning approach to localizing the origin of ventricular tachycardia using 12-lead electrocardiograms.

BACKGROUND: Machine learning models may help localize the site of origin of ventricular tachycardia (VT) using 12-lead electrocardiograms. However, population-based models suffer from inter-subject anatomical variations within ECG data, while patient-specific models face the open challenge of what pacing data to collect for training. METHODS: This study presents and validates the first hybrid model that combines population and patient-specific machine learning for rapid "computer-guided pace-mapping". A population-based deep learning model was first trained offline to disentangle inter-subject variations and regionalize the site of VT origin. Given a new patient with a target VT, an on-line patient-specific model -- after being initialized by the population-based prediction -- was then built in real time by actively suggesting where to pace next and improving the prediction with each added pacing data, progressively guiding pace-mapping towards the site of VT origin. RESULTS: The population model was trained on pace-mapping data from 38 patients and the patient-specific model was subsequently tuned on one patient. The resulting hybrid model was tested on a separate cohort of eight patients in localizing 1) 193 LV endocardial pacing sites, and 2) nine VTs with clinically determined exit sites. The hybrid model achieved a localization error of 5.3 ± 2.6 mm using 5.4 ± 2.5 pacing sites in localizing LV pacing sites, achieving a significantly higher accuracy with a significantly smaller amount of training sites in comparison to models without active guidance. CONCLUSION: The presented hybrid model has the potential to assist rapid pace-mapping of interventional targets in VT.