With the advance of high-throughput genotyping and sequencing technologies, it becomes feasible to comprehensive evaluate the role of massive genetic predictors in disease prediction. There exists, therefore, a critical need for developing appropriate statistical measurements to access the combined effects of these genetic variants in disease prediction. Predictiveness curve is commonly used as a graphical tool to measure the predictive ability of a risk prediction model on a single continuous biomarker. Yet, for most complex diseases, risk prediciton models are formed on multiple genetic variants. We therefore propose a multi-marker predictiveness curve and provide a non-parametric method to construct the curve for case-control studies. We further introduce a global predictiveness U and a partial predictiveness U to summarize prediction curve across the whole population and sub-population of clinical interest, respectively. We also demonstrate the connections of predictiveness curve with ROC curve and Lorenz curve. Through simulation, we compared the performance of the predictiveness U to other three summary indices: R square, Total Gain, and Average Entropy, and showed that Predictiveness U outperformed the other three indexes in terms of unbiasedness and robustness. Moreover, we simulated a series of rare-variants disease model, found partial predictiveness U performed better than global predictiveness U. Finally, we conducted a real data analysis, using predictiveness curve and predictiveness U to evaluate a risk prediction model for Nicotine Dependence.
Across various domains, the growing advocacy for open science and open-source machine learning has made an increasing number of models publicly available. These models allow practitioners to integrate them into their own contexts, reducing the need for extensive data labeling, training, and calibration. However, selecting the best model for a specific target population remains challenging due to issues like limited transferability, data heterogeneity, and the difficulty of obtaining true labels or outcomes in real-world settings. In this paper, we propose an unsupervised model aggregation method, U-aggregation, designed to integrate multiple pre-trained models for enhanced and robust performance in new populations. Unlike existing supervised model aggregation or super learner approaches, U-aggregation assumes no observed labels or outcomes in the target population. Our method addresses limitations in existing unsupervised model aggregation techniques by accommodating more realistic settings, including heteroskedasticity at both the model and individual levels, and the presence of adversarial models. Drawing on insights from random matrix theory, U-aggregation incorporates a variance stabilization step and an iterative sparse signal recovery process. These steps improve the estimation of individuals' true underlying risks in the target population and evaluate the relative performance of candidate models. We provide a theoretical investigation and systematic numerical experiments to elucidate the properties of U-aggregation. We demonstrate its potential real-world application by using U-aggregation to enhance genetic risk prediction of complex traits, leveraging publicly available models from the PGS Catalog.
Multi-task learning has emerged as a powerful machine learning paradigm for integrating data from multiple sources, leveraging similarities between tasks to improve overall model performance. However, the application of multi-task learning to real-world settings is hindered by data-sharing constraints, especially in healthcare settings. To address this challenge, we propose a flexible multi-task learning framework utilizing summary statistics from various sources. Additionally, we present an adaptive parameter selection approach based on a variant of Lepski's method, allowing for data-driven tuning parameter selection when only summary statistics are available. Our systematic non-asymptotic analysis characterizes the performance of the proposed methods under various regimes of the sample complexity and overlap. We demonstrate our theoretical findings and the performance of the method through extensive simulations. This work offers a more flexible tool for training related models across various domains, with practical implications in genetic risk prediction and many other fields.
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 bias, largely due to the prediction models being confounded by the underlying population structure, we propose a novel 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, particularly for admixed individuals.
Risk modeling with EHR data is challenging due to a lack of direct observations on the disease outcome, and the high dimensionality of the candidate predictors. In this paper, we develop a surrogate assisted semi-supervised-learning (SAS) approach to risk modeling with high dimensional predictors, leveraging a large unlabeled data on candidate predictors and surrogates of outcome, as well as a small labeled data with annotated outcomes. The SAS procedure borrows information from surrogates along with candidate predictors to impute the unobserved outcomes via a sparse working imputation model with moment conditions to achieve robustness against mis-specification in the imputation model and a one-step bias correction to enable interval estimation for the predicted risk. We demonstrate that the SAS procedure provides valid inference for the predicted risk derived from a high dimensional working model, even when the underlying risk prediction model is dense and the risk model is mis-specified. We present an extensive simulation study to demonstrate the superiority of our SSL approach compared to existing supervised methods. We apply the method to derive genetic risk prediction of type-2 diabetes mellitus using a EHR biobank cohort.