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1. Ensuring electronic medical record simulation through better training, modeling, and evaluation

   https://doi.org/10.1093/jamia/ocz161  

   Zhang, Ziqi ; Yan, Chao ; Mesa, Diego A. ; Sun, Jimeng ; Malin, Bradley A. ( October 2019 , Journal of the American Medical Informatics Association)

   Electronic medical records (EMRs) can support medical research and discovery, but privacy risks limit the sharing of such data on a wide scale. Various approaches have been developed to mitigate risk, including record simulation via generative adversarial networks (GANs). While showing promise in certain application domains, GANs lack a principled approach for EMR data that induces subpar simulation. In this article, we improve EMR simulation through a novel pipeline that (1) enhances the learning model, (2) incorporates evaluation criteria for data utility that informs learning, and (3) refines the training process.

   We propose a new electronic health record generator using a GAN with a Wasserstein divergence and layer normalization techniques. We designed 2 utility measures to characterize similarity in the structural properties of real and simulated EMRs in the original and latent space, respectively. We applied a filtering strategy to enhance GAN training for low-prevalence clinical concepts. We evaluated the new and existing GANs with utility and privacy measures (membership and disclosure attacks) using billing codes from over 1 million EMRs at Vanderbilt University Medical Center.

   The proposed model outperformed the state-of-the-art approaches with significant improvement in retaining the nature of real records, including prediction performance and structural properties, without sacrificing privacy. Additionally, the filtering strategy achieved higher utility when the EMR training dataset was small.

   These findings illustrate that EMR simulation through GANs can be substantially improved through more appropriate training, modeling, and evaluation criteria.

    

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2. Sensitivity analyses in longitudinal clinical trials via distributional imputation

   https://doi.org/10.1177/09622802221135251  

   Liu, Siyi ; Yang, Shu ; Zhang, Yilong ; Liu, Guanghan ( November 2022 , Statistical Methods in Medical Research)

   Missing data is inevitable in longitudinal clinical trials. Conventionally, the missing at random assumption is assumed to handle missingness, which however is unverifiable empirically. Thus, sensitivity analyses are critically important to assess the robustness of the study conclusions against untestable assumptions. Toward this end, regulatory agencies and the pharmaceutical industry use sensitivity models such as return-to-baseline, control-based, and washout imputation, following the ICH E9(R1) guidance. Multiple imputation is popular in sensitivity analyses; however, it may be inefficient and result in an unsatisfying interval estimation by Rubin’s combining rule. We propose distributional imputation in sensitivity analysis, which imputes each missing value by samples from its target imputation model given the observed data. Drawn on the idea of Monte Carlo integration, the distributional imputation estimator solves the mean estimating equations of the imputed dataset. It is fully efficient with theoretical guarantees. Moreover, we propose weighted bootstrap to obtain a consistent variance estimator, taking into account the variabilities due to model parameter estimation and target parameter estimation. The superiority of the distributional imputation framework is validated in the simulation study and an antidepressant longitudinal clinical trial.

    

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3. VIGAN: Missing view imputation with generative adversarial networks

   https://doi.org/10.1109/BigData.2017.8257992  

   Shang, Chao ; Palmer, Aaron ; Sun, Jiangwen ; Chen, Ko-Shin ; Lu, Jin ; Bi, Jinbo ( December 2017 , 2017 IEEE International Conference on Big Data (Big Data))

   In an era when big data are becoming the norm, there is less concern with the quantity but more with the quality and completeness of the data. In many disciplines, data are collected from heterogeneous sources, resulting in multi-view or multi-modal datasets. The missing data problem has been challenging to address in multi-view data analysis. Especially, when certain samples miss an entire view of data, it creates the missing view problem. Classic multiple imputations or matrix completion methods are hardly effective here when no information can be based on in the specific view to impute data for such samples. The commonly-used simple method of removing samples with a missing view can dramatically reduce sample size, thus diminishing the statistical power of a subsequent analysis. In this paper, we propose a novel approach for view imputation via generative adversarial networks (GANs), which we name by VIGAN. This approach first treats each view as a separate domain and identifies domain-to-domain mappings via a GAN using randomly-sampled data from each view, and then employs a multi-modal denoising autoencoder (DAE) to reconstruct the missing view from the GAN outputs based on paired data across the views. Then, by optimizing the GAN and DAE jointly, our model enables the knowledge integration for domain mappings and view correspondences to effectively recover the missing view. Empirical results on benchmark datasets validate the VIGAN approach by comparing against the state of the art. The evaluation of VIGAN in a genetic study of substance use disorders further proves the effectiveness and usability of this approach in life science. 

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4. Ensemble Generative Adversarial Imputation Network with Selective Multi-Generator (ESM-GAIN) for Missing Data Imputation

   https://doi.org/10.1109/CASE49997.2022.9926629  

   Li, Yuxuan ; Dogan, Ayse ; Liu, Chenang ( August 2022 , 2022 IEEE 18th International Conference on Automation Science and Engineering (CASE))

   As a pervasive issue, missing data may influence the data modeling performance and lead to more difficulties of completing the desired tasks. Many approaches have been developed for missing data imputation. Recently, by taking advantage of the emerging generative adversarial network (GAN), an effective missing data imputation approach termed generative adversarial imputation nets (GAIN) was developed. However, its modeling architecture may still lead to significant imputation bias. In addition, with the GAN structure, the training process of GAIN may be unstable and the imputation variation may be high. Hence, to address these two limitations, the ensemble GAIN with selective multi-generator (ESM-GAIN) is proposed to improve the imputation accuracy and robustness. The contributions of the proposed ESM-GAIN consist of two aspects: (1) a selective multi-generation framework is proposed to identify high-quality imputations; (2) an ensemble learning framework is incorporated for GAIN imputation to improve the imputation robustness. The effectiveness of the proposed ESM-GAIN is validated by both numerical simulation and two real-world breast cancer datasets. 

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5. DeepGAMI: deep biologically guided auxiliary learning for multimodal integration and imputation to improve genotype–phenotype prediction

   https://doi.org/10.1186/s13073-023-01248-6  

   Chandrashekar, Pramod Bharadwaj ; Alatkar, Sayali ; Wang, Jiebiao ; Hoffman, Gabriel E. ; He, Chenfeng ; Jin, Ting ; Khullar, Saniya ; Bendl, Jaroslav ; Fullard, John F. ; Roussos, Panos ; et al ( October 2023 , Genome Medicine)

   Genotypes are strongly associated with disease phenotypes, particularly in brain disorders. However, the molecular and cellular mechanisms behind this association remain elusive. With emerging multimodal data for these mechanisms, machine learning methods can be applied for phenotype prediction at different scales, but due to the black-box nature of machine learning, integrating these modalities and interpreting biological mechanisms can be challenging. Additionally, the partial availability of these multimodal data presents a challenge in developing these predictive models.

   To address these challenges, we developed DeepGAMI, an interpretable neural network model to improve genotype–phenotype prediction from multimodal data. DeepGAMI leverages functional genomic information, such as eQTLs and gene regulation, to guide neural network connections. Additionally, it includes an auxiliary learning layer for cross-modal imputation allowing the imputation of latent features of missing modalities and thus predicting phenotypes from a single modality. Finally, DeepGAMI uses integrated gradient to prioritize multimodal features for various phenotypes.

   We applied DeepGAMI to several multimodal datasets including genotype and bulk and cell-type gene expression data in brain diseases, and gene expression and electrophysiology data of mouse neuronal cells. Using cross-validation and independent validation, DeepGAMI outperformed existing methods for classifying disease types, and cellular and clinical phenotypes, even using single modalities (e.g., AUC score of 0.79 for Schizophrenia and 0.73 for cognitive impairment in Alzheimer’s disease).

   We demonstrated that DeepGAMI improves phenotype prediction and prioritizes phenotypic features and networks in multiple multimodal datasets in complex brains and brain diseases. Also, it prioritized disease-associated variants, genes, and regulatory networks linked to different phenotypes, providing novel insights into the interpretation of gene regulatory mechanisms. DeepGAMI is open-source and available for general use.

    

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