Despite significant progress in vaccine research, the level of protection provided by vaccination can vary significantly across individuals. As a result, understanding immunologic variation across individuals in response to vaccination is important for developing next-generation efficacious vaccines. Accurate outcome prediction and identification of predictive biomarkers would represent a significant step towards this goal. Moreover, in early phase vaccine clinical trials, small datasets are prevalent, raising the need and challenge of building a robust and explainable prediction model that can reveal heterogeneity in small datasets. We propose a new model named Generative Mixture of Logistic Regression (GeM-LR), which combines characteristics of both a generative and a discriminative model. In addition, we propose a set of model selection strategies to enhance the robustness and interpretability of the model. GeM-LR extends a linear classifier to a non-linear classifier without losing interpretability and empowers the notion of predictive clustering for characterizing data heterogeneity in connection with the outcome variable. We demonstrate the strengths and utility of GeM-LR by applying it to data from several studies. GeM-LR achieves better prediction results than other popular methods while providing interpretations at different levels.

Multi-view data can be generated from diverse sources, by different technologies, and in multiple modalities. In various fields, integrating information from multi-view data has pushed the frontier of discovery. In this paper, we develop a new approach for multi-view clustering, which overcomes the limitations of existing methods such as the need of pooling data across views, restrictions on the clustering algorithms allowed within each view, and the disregard for complementary information between views. Our new method, called CPS-merge analysis, merges clusters formed by the Cartesian product of single-view cluster labels, guided by the principle of maximizing clustering stability as evaluated by CPS analysis. In addition, we introduce measures to quantify the contribution of each view to the formation of any cluster. CPS-merge analysis can be easily incorporated into an existing clustering pipeline because it only requires single-view cluster labels instead of the original data. We can thus readily apply advanced single-view clustering algorithms. Importantly, our approach accounts for both consensus and complementary effects between different views, whereas existing ensemble methods focus on finding a consensus for multiple clustering results, implying that results from different views are variations of one clustering structure. Through experiments on single-cell datasets, we demonstrate that our approach frequently outperforms other state-of-the-art methods.

Controlling False Discovery Rate (FDR) while leveraging the side information of multiple hypothesis testing is an emerging research topic in modern data science. Existing methods rely on the test-level covariates while ignoring metrics about test-level covariates. This strategy may not be optimal for complex large-scale problems, where indirect relations often exist among test-level covariates and auxiliary metrics or covariates. We incorporate auxiliary covariates among test-level covariates in a deep Black-Box framework (named as NeurT-FDR) which boosts statistical power and controls FDR for multiple hypothesis testing. Our method parametrizes the test-level covariates as a neural network and adjusts the auxiliary covariates through a regression framework, which enables flexible handling of high-dimensional features as well as efficient end-to-end optimization. We show that NeurT-FDR makes substantially more discoveries in three real datasets compared to competitive baselines.

MOTIVATION: Cluster analysis is widely used to identify interesting subgroups in biomedical data. Since true class labels are unknown in the unsupervised setting, it is challenging to validate any cluster obtained computationally, an important problem barely addressed by the research community. RESULTS: We have developed a toolkit called covering point set (CPS) analysis to quantify uncertainty at the levels of individual clusters and overall partitions. Functions have been developed to effectively visualize the inherent variation in any cluster for data of high dimension, and provide more comprehensive view on potentially interesting subgroups in the data. Applying to three usage scenarios for biomedical data, we demonstrate that CPS analysis is more effective for evaluating uncertainty of clusters comparing to state-of-the-art measurements. We also showcase how to use CPS analysis to select data generation technologies or visualization methods. AVAILABILITY AND IMPLEMENTATION: The method is implemented in an R package called OTclust, available on CRAN. CONTACT: [email protected] or [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Human Endogenous Retrovirus type K (HERV-K) is the only HERV known to be insertionally polymorphic; not all individuals have a retrovirus at a specific genomic location. It is possible that HERV-Ks contribute to human disease because people differ in both number and genomic location of these retroviruses. Indeed viral transcripts, proteins, and antibody against HERV-K are detected in cancers, auto-immune, and neurodegenerative diseases. However, attempts to link a polymorphic HERV-K with any disease have been frustrated in part because population prevalence of HERV-K provirus at each polymorphic site is lacking and it is challenging to identify closely related elements such as HERV-K from short read sequence data. We present an integrated and computationally robust approach that uses whole genome short read data to determine the occupation status at all sites reported to contain a HERV-K provirus. Our method estimates the proportion of fixed length genomic sequence (k-mers) from whole genome sequence data matching a reference set of k-mers unique to each HERV-K locus and applies mixture model-based clustering of these values to account for low depth sequence data. Our analysis of 1000 Genomes Project Data (KGP) reveals numerous differences among the five KGP super-populations in the prevalence of individual and co-occurring HERV-K proviruses; we provide a visualization tool to easily depict the proportion of the KGP populations with any combination of polymorphic HERV-K provirus. Further, because HERV-K is insertionally polymorphic, the genome burden of known polymorphic HERV-K is variable in humans; this burden is lowest in East Asian (EAS) individuals. Our study identifies population-specific sequence variation for HERV-K proviruses at several loci. We expect these resources will advance research on HERV-K contributions to human diseases.

It has been recently shown that deep neural networks (DNNs) are susceptible to a particular type of attack that exploits a fundamental flaw in their design. This attack consists of generating particular synthetic examples referred to as adversarial samples. These samples are constructed by slightly manipulating real data-points that change "fool" the original DNN model, forcing it to misclassify previously correctly classified samples with high confidence. Many believe addressing this flaw is essential for DNNs to be used in critical applications such as cyber security. Previous work has shown that learning algorithms that enhance the robustness of DNN models all use the tactic of "security through obscurity". This means that security can be guaranteed only if one can obscure the learning algorithms from adversaries. Once the learning technique is disclosed, DNNs protected by these defense mechanisms are still susceptible to adversarial samples. In this work, we investigate by examining how previous research dealt with this and propose a generic approach to enhance a DNN's resistance to adversarial samples. More specifically, our approach integrates a data transformation module with a DNN, making it robust even if we reveal the underlying learning algorithm. To demonstrate the generality of our proposed approach and its potential for handling cyber security applications, we evaluate our method and several other existing solutions on datasets publicly available, such as a large scale malware dataset and MNIST and IMDB datasets. Our results indicate that our approach typically provides superior classification performance and robustness to attacks compared with state-of-art solutions.

Understanding and interpreting how machine learning (ML) models make decisions have been a big challenge. While recent research has proposed various technical approaches to provide some clues as to how an ML model makes individual predictions, they cannot provide users with an ability to inspect a model as a complete entity. In this work, we propose a novel technical approach that augments a Bayesian non-parametric regression mixture model with multiple elastic nets. Using the enhanced mixture model, we can extract generalizable insights for a target model through a global approximation. To demonstrate the utility of our approach, we evaluate it on different ML models in the context of image recognition. The empirical results indicate that our proposed approach not only outperforms the state-of-the-art techniques in explaining individual decisions but also provides users with an ability to discover the vulnerabilities of the target ML models.

Large-scale data containing multiple important rare clusters, even at moderately high dimensions, pose challenges for existing clustering methods. To address this issue, we propose a new mixture model called Hidden Markov Model on Variable Blocks (HMM-VB) and a new mode search algorithm called Modal Baum-Welch (MBW) for mode-association clustering. HMM-VB leverages prior information about chain-like dependence among groups of variables to achieve the effect of dimension reduction. In case such a dependence structure is unknown or assumed merely for the sake of parsimonious modeling, we develop a recursive search algorithm based on BIC to optimize the formation of ordered variable blocks. The MBW algorithm ensures the feasibility of clustering via mode association, achieving linear complexity in terms of the number of variable blocks despite the exponentially growing number of possible state sequences in HMM-VB. In addition, we provide theoretical investigations about the identifiability of HMM-VB as well as the consistency of our approach to search for the block partition of variables in a special case. Experiments on simulated and real data show that our proposed method outperforms other widely used methods.

Nowadays, auto insurance companies set personalized insurance rate based on data gathered directly from their customers' cars. In this paper, we show such a personalized insurance mechanism -- wildly adopted by many auto insurance companies -- is vulnerable to exploit. In particular, we demonstrate that an adversary can leverage off-the-shelf hardware to manipulate the data to the device that collects drivers' habits for insurance rate customization and obtain a fraudulent insurance discount. In response to this type of attack, we also propose a defense mechanism that escalates the protection for insurers' data collection. The main idea of this mechanism is to augment the insurer's data collection device with the ability to gather unforgeable data acquired from the physical world, and then leverage these data to identify manipulated data points. Our defense mechanism leveraged a statistical model built on unmanipulated data and is robust to manipulation methods that are not foreseen previously. We have implemented this defense mechanism as a proof-of-concept prototype and tested its effectiveness in the real world. Our evaluation shows that our defense mechanism exhibits a false positive rate of 0.032 and a false negative rate of 0.013.

Flow cytometry is the prototypical assay for multi-parameter single cell analysis, and is essential in vaccine and biomarker research for the enumeration of antigen-specific lymphocytes that are often found in extremely low frequencies (0.1% or less). Standard analysis of flow cytometry data relies on visual identification of cell subsets by experts, a process that is subjective and often difficult to reproduce. An alternative and more objective approach is the use of statistical models to identify cell subsets of interest in an automated fashion. Two specific challenges for automated analysis are to detect extremely low frequency event subsets without biasing the estimate by pre-processing enrichment, and the ability to align cell subsets across multiple data samples for comparative analysis. In this manuscript, we develop hierarchical modeling extensions to the Dirichlet Process Gaussian Mixture Model (DPGMM) approach we have previously described for cell subset identification, and show that the hierarchical DPGMM (HDPGMM) naturally generates an aligned data model that captures both commonalities and variations across multiple samples. HDPGMM also increases the sensitivity to extremely low frequency events by sharing information across multiple samples analyzed simultaneously. We validate the accuracy and reproducibility of HDPGMM estimates of antigen-specific T cells on clinically relevant reference peripheral blood mononuclear cell (PBMC) samples with known frequencies of antigen-specific T cells. These cell samples take advantage of retrovirally TCR-transduced T cells spiked into autologous PBMC samples to give a defined number of antigen-specific T cells detectable by HLA-peptide multimer binding. We provide open source software that can take advantage of both multiple processors and GPU-acceleration to perform the numerically-demanding computations. We show that hierarchical modeling is a useful probabilistic approach that can provide a consistent labeling of cell subsets and increase the sensitivity of rare event detection in the context of quantifying antigen-specific immune responses.