Collecting gold-standard phenotype data via manual extraction is typically labor-intensive and slow, whereas automated computational phenotypes (ACPs) offer a systematic and much faster alternative. However, simply replacing the gold-standard with ACPs, without acknowledging their differences, could lead to biased results and misleading conclusions. Motivated by the complexity of incorporating ACPs while maintaining the validity of downstream analyses, in this paper, we consider a semi-supervised learning setting that consists of both labeled data (with gold-standard) and unlabeled data (without gold-standard), under the covariate shift framework. We develop doubly robust and semiparametrically efficient estimators that leverage ACPs for general target parameters in the unlabeled and combined populations. In addition, we carefully analyze the efficiency gains achieved by incorporating ACPs, comparing scenarios with and without their inclusion. Notably, we identify that ACPs for the unlabeled data, instead of for the labeled data, drive the enhanced efficiency gains. To validate our theoretical findings, we conduct comprehensive synthetic experiments and apply our method to multiple real-world datasets, confirming the practical advantages of our approach.

Denoising diffusion probabilistic models (DDPMs) have achieved unprecedented success in computer vision. However, they remain underutilized in medical imaging, a field crucial for disease diagnosis and treatment planning. This is primarily due to the high computational cost associated with the use of large number of time steps (e.g., 1,000) in diffusion processes. Training a diffusion model on medical images typically takes days to weeks, while sampling each image volume takes minutes to hours. To address this challenge, we introduce Fast-DDPM, a simple yet effective approach capable of simultaneously improving training speed, sampling speed, and generation quality. Unlike DDPM, which trains the image denoiser across 1,000 time steps, Fast-DDPM trains and samples using only 10 time steps. The key to our method lies in aligning the training and sampling procedures to optimize time-step utilization. Specifically, we introduced two efficient noise schedulers with 10 time steps: one with uniform time step sampling and another with non-uniform sampling. We evaluated Fast-DDPM across three medical image-to-image generation tasks: multi-image super-resolution, image denoising, and image-to-image translation. Fast-DDPM outperformed DDPM and current state-of-the-art methods based on convolutional networks and generative adversarial networks in all tasks. Additionally, Fast-DDPM reduced the training time to 0.2× and the sampling time to 0.01× compared to DDPM.

The recent development of artificial intelligence (AI) technology, especially the advance of deep neural network (DNN) technology, has revolutionized many fields. While DNN plays a central role in modern AI technology, it has rarely been used in genetic data analysis due to analytical and computational challenges brought by high-dimensional genetic data and an increasing number of samples. To facilitate the use of AI in genetic data analysis, we developed a C++ package, AIGen, based on two newly developed neural networks (i.e. kernel neural networks and functional neural networks) that are capable of modeling complex genotype-phenotype relationships (e.g. interactions) while providing robust performance against high-dimensional genetic data. Moreover, computationally efficient algorithms (e.g. a minimum norm quadratic unbiased estimation approach and batch training) are implemented in the package to accelerate the computation, making them computationally efficient for analyzing large-scale datasets with thousands or even millions of samples. By applying AIGen to the UK Biobank dataset, we demonstrate that it can efficiently analyze large-scale genetic data, attain improved accuracy, and maintain robust performance. Availability: AIGen is developed in C++ and its source code, along with reference libraries, is publicly accessible on GitHub at https://github.com/TingtHou/AIGen.

With the increasing adoption of electronic health records, there is an increasing interest in developing individualized treatment rules, which recommend treatments according to patients' characteristics, from large observational data. However, there is a lack of valid inference procedures for such rules developed from this type of data in the presence of high-dimensional covariates. In this work, we develop a penalized doubly robust method to estimate the optimal individualized treatment rule from high-dimensional data. We propose a split-and-pooled de-correlated score to construct hypothesis tests and confidence intervals. Our proposal adopts the data splitting to conquer the slow convergence rate of nuisance parameter estimations, such as non-parametric methods for outcome regression or propensity models. We establish the limiting distributions of the split-and-pooled de-correlated score test and the corresponding one-step estimator in high-dimensional setting. Simulation and real data analysis are conducted to demonstrate the superiority of the proposed method.

Identification of cancer subtypes plays an important role in revealing useful insights into disease pathogenesis and advancing personalized therapy. The recent development of high-throughput sequencing technologies has enabled the rapid collection of multi-platform genomic data (e.g., gene expression, miRNA expression, and DNA methylation) for the same set of tumor samples. Although numerous integrative clustering approaches have been developed to analyze cancer data, few of them are particularly designed to exploit both deep intrinsic statistical properties of each input modality and complex cross-modality correlations among multi-platform input data. In this paper, we propose a new machine learning model, called multimodal deep belief network (DBN), to cluster cancer patients from multi-platform observation data. In our integrative clustering framework, relationships among inherent features of each single modality are first encoded into multiple layers of hidden variables, and then a joint latent model is employed to fuse common features derived from multiple input modalities. A practical learning algorithm, called contrastive divergence (CD), is applied to infer the parameters of our multimodal DBN model in an unsupervised manner. Tests on two available cancer datasets show that our integrative data analysis approach can effectively extract a unified representation of latent features to capture both intra- and cross-modality correlations, and identify meaningful disease subtypes from multi-platform cancer data. In addition, our approach can identify key genes and miRNAs that may play distinct roles in the pathogenesis of different cancer subtypes. Among those key miRNAs, we found that the expression level of miR-29a is highly correlated with survival time in ovarian cancer patients. These results indicate that our multimodal DBN based data analysis approach may have practical applications in cancer pathogenesis studies and provide useful guidelines for personalized cancer therapy.