• Introduces DepAD for using variable dependencies for detecting anomalies. • Reframes unsupervised detection as supervised feature selection and prediction. • Evaluates DepAD against nine state-of-the-art methods on 32 datasets. • DepAD outperforms in detecting anomalies with better interpretability. • Demonstrates new insights and interpretations for detected anomalies. Anomaly detection is crucial for identifying unusual behaviors in data, which often provide valuable insights. This paper introduces Dependency-based Anomaly Detection (DepAD), a general and modular framework that leverages variable dependencies to uncover meaningful anomalies with improved interpretability. DepAD reframes unsupervised anomaly detection as a sequence of supervised feature selection and prediction tasks, enabling users to tailor detection methods to their data and domain. We systematically evaluate 125 DepAD algorithm variants across 32 real-world datasets, combining different off-the-shelf feature selection and prediction techniques. We compare DepAD with twelve state-of-the-art anomaly detection methods and demonstrate its consistent superior performance. Furthermore, we demonstrate that DepAD provides intuitive and informative interpretations of detected anomalies, highlighting its utility in practical applications.

In high-stakes domains such as healthcare, finance, and law, the need for explainable AI is critical. Traditional methods for generating attribution maps, including white-box approaches relying on gradients and black-box techniques that perturb inputs, face challenges like gradient vanishing, blurred attributions, and computational inefficiencies. To overcome these limitations, we introduce a novel approach that leverages diffusion models within the framework of Information Bottleneck (IB) theory. By utilizing the Gaussian noise from diffusion models, we connect the information bottleneck with the Minimum Mean Squared Error (MMSE) from classical information theory, enabling precise calculation of mutual information. This connection leads to a new loss function that minimizes the Signal-to-Noise Ratio (SNR), facilitating efficient optimization and producing high-resolution, pixel-level attribution maps. Our method achieves greater clarity and accuracy in attributions than existing techniques, requiring significantly fewer pixel values to reach the necessary predictive confidence. This work demonstrates the power of diffusion models in advancing explainable AI, particularly in identifying critical input features with high precision.

Zero-inflated data pose significant challenges in precipitation forecasting due to the predominance of zeros with sparse non-zero events. To address this, we propose the Zero Inflation Diffusion Framework (ZIDF), which integrates Gaussian perturbation for smoothing zero-inflated distributions, Transformer-based prediction for capturing temporal patterns, and diffusion-based denoising to restore the original data structure. In our experiments, we use observational precipitation data collected from South Australia along with synthetically generated zero-inflated data. Results show that ZIDF demonstrates significant performance improvements over multiple state-of-the-art precipitation forecasting models, achieving up to 56.7% reduction in MSE and 21.1% reduction in MAE relative to the baseline Non-stationary Transformer. These findings highlight ZIDF’s ability to robustly handle sparse time series data and suggest its potential generalizability to other domains where zero inflation is a key challenge.

Global Climate Models (GCMs) are crucial for predicting future climate changes by simulating the Earth systems. However, GCM outputs exhibit systematic biases due to model uncertainties, parameterization simplifications, and inadequate representation of complex climate phenomena. Traditional bias correction methods, which rely on historical observation data and statistical techniques, often neglect unobserved confounders, leading to biased results. This paper proposes a novel bias correction approach to utilize both GCM and observational data to learn a factor model that captures multi-cause latent confounders. Inspired by recent advances in causality based time series deconfounding, our method first constructs a factor model to learn latent confounders from historical data and then applies them to enhance the bias correction process using advanced time series forecasting models. The experimental results demonstrate significant improvements in the accuracy of precipitation outputs. By addressing unobserved confounders, our approach offers a robust and theoretically grounded solution for climate model bias correction.

Long COVID, or Post-Acute Sequelae of SARS-CoV-2 infection (PASC), affects an estimated 10-20% of COVID-19 patients and presents persistent multisystemic symptoms. Although demographic and clinical factors, such as age, sex, and comorbidities, contribute to risk, the genetic mechanisms underlying this risk remain poorly defined. To address this gap, we developed a multi-omics framework that integrates Transcriptome-Wide Mendelian Randomization (TWMR), Control Theory (CT), Expression Quantitative Trait Loci (eQTL), Genome-Wide Association Studies (GWAS), RNA sequencing (RNA-seq), and Protein-Protein Interaction (PPI) network to identify putative causal genes and network drivers in Long COVID. Our approach prioritized 32 candidate genes, including 19 previously reported and 13 novel, with roles in the SARS-CoV-2 response, viral carcinogenesis, immune regulation, and cell cycle control. Enrichment analyses revealed a shared genetic architecture in syndromic, metabolic, autoimmune, and connective tissue disorders. Using causal gene expression profiles, we identified three distinct symptom-based subtypes of Long COVID, providing information on the heterogeneity of disease mechanisms and clinical presentation. Finally, we developed an open-source Shiny application for interactive exploration of these findings. Together, this integrative framework highlights novel causal mechanisms and therapeutic targets, advancing precision medicine strategies for Long COVID.

Predicting breast cancer prognosis helps improve the treatment and management of the disease. In recent decades, many prediction models have been developed for breast cancer prognosis. A common assumption made by these models is that the test and training data follow the same distribution. However, due to the heterogeneity of breast cancer and differences in the environments where the data are collected, the distribution of the test data may shift from that of the training data. Existing methods may not provide stable predictions when data distribution shifts occur. In this paper, we present a novel method for stable breast cancer prognosis in situations with data distribution shifts. Our model, known as Deep Global Balancing Cox regression (DGBCox), is based on the causal inference theory. In DGBCox, initial high-dimensional gene expression data is transferred to latent representations by a deep autoencoder neural network. After balancing the latent representations using a proposed causality-based approach, causal latent features are selected for breast cancer prognosis. We apply DGBCox to 12 test datasets from different breast cancer studies. The results show that DGBCox outperforms benchmark methods in terms of both prediction accuracy and stability.

Latent confounders are a fundamental challenge for inferring causal effects from observational data. The instrumental variable (IV) approach is a practical way to address this challenge. Existing IV-based estimators need a known IV or other strong assumptions, such as the existence of two or more IVs in the system, which limits the application of the IV approach. In this article, we consider a relaxed requirement, which assumes there is an IV proxy in the system without knowing which variable is the proxy. We propose a variational autoencoder (VAE)-based disentangled representation learning method to learn an IV representation from a dataset with latent confounders and then utilize the IV representation to obtain an unbiased estimation of the causal effect from the data. Extensive experiments on synthetic and real-world data have demonstrated that the proposed algorithm outperforms the existing IV-based estimators and VAE-based estimators.

Causal inference from longitudinal observational data is a challenging problem due to the difficulty in correctly identifying the time-dependent confounders, especially in the presence of latent time-dependent confounders. Instrumental variable (IV) is a powerful tool for addressing the latent confounders issue, but the traditional IV technique cannot deal with latent time-dependent confounders in longitudinal studies. In this work, we propose a novel Time-dependent Instrumental Factor Model (TIFM) for time-varying causal effect estimation from data with latent time-dependent confounders. At each time-step, the proposed TIFM method employs the Recurrent Neural Network (RNN) architecture to infer latent IV, and then uses the inferred latent IV factor for addressing the confounding bias caused by the latent time-dependent confounders. We provide a theoretical analysis for the proposed TIFM method regarding causal effect estimation in longitudinal data. Extensive evaluation with synthetic datasets demonstrates the effectiveness of TIFM in addressing causal effect estimation over time. We further apply TIFM to a climate dataset to showcase the potential of the proposed method in tackling real-world problems.

This paper studies the challenging problem of estimating causal effects from observational data, in the presence of unobserved confounders. The two-stage least square (TSLS) method and its variants with a standard instrumental variable (IV) are commonly used to eliminate confounding bias, including the bias caused by unobserved confounders, but they rely on the linearity assumption. Besides, the strict condition of unconfounded instruments posed on a standard IV is too strong to be practical. To address these challenging and practical problems of the standard IV method (linearity assumption and the strict condition), in this paper, we use a conditional IV (CIV) to relax the unconfounded instrument condition of standard IV and propose a non-linear \underline{CIV} regression with \underline{C}onfounding \underline{B}alancing \underline{R}epresentation \underline{L}earning, CBRL.CIV, for jointly eliminating the confounding bias from unobserved confounders and balancing the observed confounders, without the linearity assumption. We theoretically demonstrate the soundness of CBRL.CIV. Extensive experiments on synthetic and two real-world datasets show the competitive performance of CBRL.CIV against state-of-the-art IV-based estimators and superiority in dealing with the non-linear situation.

Instrumental variable (IV) is a powerful approach to inferring the causal effect of a treatment on an outcome of interest from observational data even when there exist latent confounders between the treatment and the outcome. However, existing IV methods require that an IV is selected and justified with domain knowledge. An invalid IV may lead to biased estimates. Hence, discovering a valid IV is critical to the applications of IV methods. In this article, we study and design a data-driven algorithm to discover valid IVs from data under mild assumptions. We develop the theory based on partial ancestral graphs (PAGs) to support the search for a set of candidate ancestral IVs (AIVs), and for each possible AIV, the identification of its conditioning set. Based on the theory, we propose a data-driven algorithm to discover a pair of IVs from data. The experiments on synthetic and real-world datasets show that the developed IV discovery algorithm estimates accurate estimates of causal effects in comparison with the state-of-the-art IV-based causal effect estimators.

The instrumental variable (IV) approach is a widely used way to estimate the causal effects of a treatment on an outcome of interest from observational data with latent confounders. A standard IV is expected to be related to the treatment variable and independent of all other variables in the system. However, it is challenging to search for a standard IV from data directly due to the strict conditions. The conditional IV (CIV) method has been proposed to allow a variable to be an instrument conditioning on a set of variables, allowing a wider choice of possible IVs and enabling broader practical applications of the IV approach. Nevertheless, there is not a data-driven method to discover a CIV and its conditioning set directly from data. To fill this gap, in this paper, we propose to learn the representations of the information of a CIV and its conditioning set from data with latent confounders for average causal effect estimation. By taking advantage of deep generative models, we develop a novel data-driven approach for simultaneously learning the representation of a CIV from measured variables and generating the representation of its conditioning set given measured variables. Extensive experiments on synthetic and real-world datasets show that our method outperforms the existing IV methods.

Researchers have developed various visualization techniques, such as attribution maps, to understand which parts of an input contribute most to a model’s decision. However, existing methods often produce disparate results and may lack human-perceptual interpretability. In this work, we propose Relevance-IBA, a novel approach that combines the strengths of Information Bottleneck Attribution (IBA) and Layer-wise Relevance Propagation’s (LRP) method to estimate more accurate and human-perceptually interpretable attribution maps. Our method accentuates the contours and subtle details of the identified object, making the model’s decisions more intuitively understandable. Additionally, we introduce a segmentation-oriented evaluation technique, which assesses the capacity of interpretability methods by emphasizing the most important pixels within an object’s boundaries. We benchmark Relevance-IBA against various methodologies, including DeepLIFT, Integrated Gradients, Guided-BP, Guided-GradCAM, IBA, and InputIBA. Our results indicate that Relevance-IBA not only boosts attribution accuracy but also prioritizes human-perceptual clarity, making it a valuable tool for interpreting complex model behaviors.

Causal relationships have been utilized in almost all disciplines, and the research into causal discovery has attracted a lot of attention in the last few years. Traditionally, causal relationships are identified by making use of interventions or randomized controlled experiments. However, conducting such experiments is often expensive or even impossible due to cost or ethical concerns. Therefore, there has been an increasing interest in discovering causal relationships based on observational data, and in the past few decades, significant contributions have been made to this field by computer scientists.

In Disability Employment Services (DES), an emerging problem is to make job survival analysis stable in unseen environments without prior knowledge of these environments. Existing survival analysis methods cannot adequately solve this problem since they assume that distribution of unseen data is similar to that observed during training. However, this assumption can be violated in practice where unanticipated events such as COVID19 and inflation can change the work and life patterns of people with disability. Models trained before the COVID19 pandemic may make unreliable job survival predictions in COVID19 or inflation situations. It is also costly and time consuming to frequently re-train and deploy the models. This paper proposes a stable survival analysis method for the DES sector without requiring prior knowledge of deployment environments. Latent representations are learned to capture non-linear relationships between relevant features and job survival time. Two reweighting stages are developed to remove censoring and conditional spurious correlations between irrelevant features and the survival outcome. The case study of Australian workers with disability shows that our method can make stable risk predictions. It can also help workers with disability determine the most effective skills for improvement to increase their job survival time. Further evaluations with public datasets show the promising stable performance of our method in other applications.

Abstract In personalised decision making, evidence is required to determine whether an action (treatment) is suitable for an individual. Such evidence can be obtained by modelling treatment effect heterogeneity in subgroups. The existing interpretable modelling methods take a top-down approach to search for subgroups with heterogeneous treatment effects and they may miss the most specific and relevant context for an individual. In this paper, we design a Treatment effect pattern (TEP) to represent treatment effect heterogeneity in data. To achieve an interpretable presentation of TEPs, we use a local causal structure around the outcome to explicitly show how those important variables are used in modelling. We also derive a formula for unbiasedly estimating the Conditional Average Causal Effect (CATE) using the local structure in our problem setting. In the discovery process, we aim at minimising heterogeneity within each subgroup represented by a pattern. We propose a bottom-up search algorithm to discover the most specific patterns fitting individual circumstances the best for personalised decision making. Experiments show that the proposed method models treatment effect heterogeneity better than three other existing tree based methods in synthetic and real world data sets.

Non-coding RNAs (ncRNAs) act as important modulators of gene expression and they have been confirmed to play critical roles in the physiology and development of malignant tumors. Understanding the synergism of multiple ncRNAs in competing endogenous RNA (ceRNA) regulation can provide important insights into the mechanisms of malignant tumors caused by ncRNA regulation. In this work, we present a framework, SCOM, for identifying ncRNA synergistic competition. We systematically construct the landscape of ncRNA synergistic competition across 31 malignant tumors, and reveal that malignant tumors tend to share hub ncRNAs rather than the ncRNA interactions involved in the synergistic competition. In addition, the synergistic competition ncRNAs (i.e. ncRNAs involved in the synergistic competition) are likely to be involved in drug resistance, contribute to distinguishing molecular subtypes of malignant tumors, and participate in immune regulation. Furthermore, SCOM can help to infer ncRNA synergistic competition across malignant tumors and uncover potential diagnostic and prognostic biomarkers of malignant tumors. Altogether, the SCOM framework (https://github.com/zhangjunpeng411/SCOM/) and the resulting web-based database SCOMdb (https://comblab.cn/SCOMdb/) serve as a useful resource for exploring ncRNA regulation and to accelerate the identification of carcinogenic biomarkers.

An emerging problem in Disability Employment Services (DES) is recommending to people with disability the right skill to upgrade and the right upgrade level to achieve maximum improvement in their employment success. This problem requires causal reasoning to estimate the individual causal effect of possible factors on the outcome to determine the most effective intervention. In this paper, we propose a causal graph based framework to solve the intervention recommendation problem for survival outcome (job retention time) and non-survival outcome (employment status). For an individual, a personalized causal graph is predicted for them. It indicates which factors affect the outcome and their causal effects at different intervention levels. Based on the causal graph, we can determine the most effective intervention for an individual, i.e., the one that can generate a maximum outcome increase. Experiments with two case studies show that our framework can help people with disability increase their employment success. Evaluations with public datasets also show the advantage of our framework in other applications.

Causal effect estimation from observational data is a challenging problem, especially with high dimensional data and in the presence of unobserved variables. The available data-driven methods for tackling the problem either provide an estimation of the bounds of a causal effect (i.e., nonunique estimation) or have low efficiency. The major hurdle for achieving high efficiency while trying to obtain unique and unbiased causal effect estimation is how to find a proper adjustment set for confounding control in a fast way, given the huge covariate space and considering unobserved variables. In this paper, we approach the problem as a local search task for finding valid adjustment sets in data. We establish the theorems to support the local search for adjustment sets, and we show that unique and unbiased estimation can be achieved from observational data even when there exist unobserved variables. We then propose a data-driven algorithm that is fast and consistent under mild assumptions. We also make use of a frequent pattern mining method to further speed up the search of minimal adjustment sets for causal effect estimation. Experiments conducted on extensive synthetic and real-world datasets demonstrate that the proposed algorithm outperforms the state-of-the-art criteria/estimators in both accuracy and time-efficiency.

Causal effect estimation from observational data is a crucial but challenging task. Currently, only a limited number of data-driven causal effect estimation methods are available. These methods either provide only a bound estimation of causal effects of treatment on the outcome or generate a unique estimation of the causal effect but making strong assumptions on data and having low efficiency. In this article, we identify a problem setting with the Cause Or Spouse of the treatment Only (COSO) variable assumption and propose an approach to achieving a unique and unbiased estimation of causal effects from data with hidden variables. For the approach, we have developed the theorems to support the discovery of the proper covariate sets for confounding adjustment (adjustment sets). Based on the theorems, two algorithms are proposed for finding the proper adjustment sets from data with hidden variables to obtain unbiased and unique causal effect estimation. Experiments with synthetic datasets generated using five benchmark Bayesian networks and four real-world datasets have demonstrated the efficiency and effectiveness of the proposed algorithms, indicating the practicability of the identified problem setting and the potential of the proposed approach in real-world applications.

In Disability Employment Service (DES), DES providers are confronted with "what-if" questions to assist workers with disability in deciding which skill should be improved to increase their job retention time. For instance, what would happen to the job retention time of a worker with disability if he improved his computer skill to an advanced level? This requires counterfactual inference to estimate the counterfactuals of the survival outcome, i.e., job retention time, under different skill improvement scenarios. While exiting survival analysis techniques are not designed for counterfactual problems, current counterfactual prediction methods are assumed to work with non-survival outcomes. In this paper, we propose the Counterfactual Survival Network (CSN), a representation learning based method for counterfactual survival prediction, where both confounding and censoring biases are removed based on latent representations. Since ground truth counterfactuals are unavailable, we develop a sample specific estimator to estimate counterfactuals for training samples. These estimated counterfactual outcomes are used as pseudo ground truth to train the counterfactual prediction model. We demonstrate the benefits of our method in decision support tasks with the case study of Australian workers and three public datasets. Results show that CSN can help Australian workers with disability increase their job retention time. Our method also shows its promising performance in other applications.

Unobserved confounding is the main obstacle to causal effect estimation from observational data. Instrumental variables (IVs) are widely used for causal effect estimation when there exist latent confounders. With the standard IV method, when a given IV is valid, unbiased estimation can be obtained, but the validity requirement on a standard IV is strict and untestable. Conditional IVs have been proposed to relax the requirement of standard IVs by conditioning on a set of observed variables (known as a conditioning set for a conditional IV). However, the criterion for finding a conditioning set for a conditional IV needs a directed acyclic graph (DAG) representing the causal relationships of both observed and unobserved variables. This makes it challenging to discover a conditioning set directly from data. In this paper, by leveraging maximal ancestral graphs (MAGs) for causal inference with latent variables, we study the graphical properties of ancestral IVs, a type of conditional IVs using MAGs, and develop the theory to support data-driven discovery of the conditioning set for a given ancestral IV in data under the pretreatment variable assumption. Based on the theory, we develop an algorithm for unbiased causal effect estimation with a given ancestral IV and observational data. Extensive experiments on synthetic and real-world datasets demonstrate the performance of the algorithm in comparison with existing IV methods.

Causal relationships have been utilized in almost all disciplines, and the research into causal discovery has attracted a lot of attention in the last few years. Traditionally, causal relationships are identified by making use of interventions or randomized controlled experiments. However, conducting such experiments is often expensive or even impossible due to cost or ethical concerns. Therefore, there has been an increasing interest in discovering causal relationships based on observational data, and in the past few decades, significant contributions have been made to this field by computer scientists.

In Disability Employment Services (DES), an emerging problem is recommending to disabled workers the right skill to upgrade and the right upgrade level to achieve a maximum increase in their job retention time. This problem involves causal reasoning to estimate the individual causal effect (ICE) on the survival outcome, i.e., job retention time, to determine the most effective intervention for a worker. Existing methods are not suitable to solve our problem. They are mostly developed for non-causal or non-survival challenges, while methods for causal survival analysis are under-explored. This paper proposes a representation learning method for recommending personalized interventions that can generate a maximum increase in job retention time for workers with disability. In our method, observed covariates are disentangled into latent variables based on which confounding and censoring biases are eliminated, and the ICE prediction model is built. Since true ICE values are not directly measurable in observational data, a reverse engineering technique is developed to estimate ICE for training samples. These estimated ICE values are then used as the pseudo ground truth to train the prediction model. Experiments with a case study of Australian workers with disability show that by adopting personalized interventions recommended by our method, disabled workers can increase their job retention time by up to 2.8 months. Additional evaluations with public datasets also show the technical strengths of our method in other applications.

Abstract A large number of covariates can have a negative impact on the quality of causal effect estimation since confounding adjustment becomes unreliable when the number of covariates is large relative to the number of samples. Propensity score is a common way to deal with a large covariate set, but the accuracy of propensity score estimation (normally done by logistic regression) is also challenged by the large number of covariates. In this paper, we prove that a large covariate set can be reduced to a lower dimensional representation which captures the complete information for adjustment in causal effect estimation. The theoretical result enables effective data-driven algorithms for causal effect estimation. Supported by the result, we develop an algorithm that employs a supervised kernel dimension reduction method to learn a lower dimensional representation from the original covariate space, and then utilises nearest neighbour matching in the reduced covariate space to impute the counterfactual outcomes to avoid the large sized covariate set problem. The proposed algorithm is evaluated on two semisynthetic and three real-world datasets and the results show the effectiveness of the proposed algorithm.

As a basic and effective tool for explanation, prediction and decision making, causal relationships have been utilized in almost all disciplines. Traditionally, causal relationships are identified by making use of interventions or randomized controlled experiments. However, conducting such experiments is often expensive or even impossible due to cost or ethical concerns. Therefore, there has been an increasing interest in discovering causal relationships based on observational data, and in the past few decades, significant contributions have been made to this field by computer scientists.

In Disability Employment Services (DES), a growing problem is recommending to disabled job seekers which skill should be upgraded and the best level for upgrading this skill to increase their employment potential most. This problem involves counterfactual reasoning to infer causal effect of factors on employment status to recommend the most effective intervention. Related methods cannot solve our problem adequately since they are developed for non-counterfactual challenges, for binary causal factors, or for randomized trials. In this paper, we present a causality-based method to tackle the problem. The method includes two stages where causal factors of employment status are first detected from data. We then combine a counterfactual reasoning framework with a machine learning approach to build an interpretable model for generating personalized recommendations. Experiments on both synthetic datasets and a real case study from a DES provider show consistent promising performance of improving employability of disabled job seekers. Results from the case study disclose effective factors and their best levels for intervention to increase employability. The most effective intervention varies among job seekers. Our model can separate job seekers by degree of employability increase. This is helpful for DES providers to allocate resources for employment assistance. Moreover, causal interpretability makes our recommendations actionable in DES business practice.

MOTIVATION: Predicting cell locations is important since with the understanding of cell locations, we may estimate the function of cells and their integration with the spatial environment. Thus, the DREAM challenge on single-cell transcriptomics required participants to predict the locations of single cells in the Drosophila embryo using single-cell transcriptomic data. RESULTS: We have developed over 50 pipelines by combining different ways of preprocessing the RNA-seq data, selecting the genes, predicting the cell locations and validating predicted cell locations, resulting in the winning methods which were ranked second in sub-challenge 1, first in sub-challenge 2 and third in sub-challenge 3. In this paper, we present an R package, SCTCwhatateam, which includes all the methods we developed and the Shiny web application to facilitate the research on single-cell spatial reconstruction. All the data and the example use cases are available in the Supplementary data.

MOTIVATION: Identifying meaningful cancer driver genes in a cohort of tumors is a challenging task in cancer genomics. Although existing studies have identified known cancer drivers, most of them focus on detecting coding drivers with mutations. It is acknowledged that non-coding drivers can regulate driver mutations to promote cancer growth. In this work, we propose a novel node importance-based network analysis (NIBNA) framework to detect coding and non-coding cancer drivers. We hypothesize that cancer drivers are crucial to the formation of community structures in cancer network, and removing them from the network greatly perturbs the network structure thereby critically affecting the functioning of the network. NIBNA detects cancer drivers using a three-step process: first, a condition-specific network is built by incorporating gene expression data and gene networks; second, the community structures in the network are estimated; and third, a centrality-based metric is applied to compute node importance. RESULTS: We apply NIBNA to the BRCA dataset, and it outperforms existing state-of-art methods in detecting coding cancer drivers. NIBNA also predicts 265 miRNA drivers, and majority of these drivers have been validated in literature. Further we apply NIBNA to detect cancer subtype-specific drivers, and several predicted drivers have been validated to be associated with cancer subtypes. Lastly, we evaluate NIBNA's performance in detecting epithelial-mesenchymal transition drivers, and we confirmed 8 coding and 13 miRNA drivers in the list of known genes. AVAILABILITY AND IMPLEMENTATION: The source code can be accessed at https://github.com/mandarsc/NIBNA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: microRNAs (miRNAs) are important gene regulators and they are involved in many biological processes, including cancer progression. Therefore, correctly identifying miRNA-mRNA interactions is a crucial task. To this end, a huge number of computational methods has been developed, but they mainly use the data at one snapshot and ignore the dynamics of a biological process. The recent development of single cell data and the booming of the exploration of cell trajectories using 'pseudotime' concept have inspired us to develop a pseudotime-based method to infer the miRNA-mRNA relationships characterizing a biological process by taking into account the temporal aspect of the process. RESULTS: We have developed a novel approach, called pseudotime causality, to find the causal relationships between miRNAs and mRNAs during a biological process. We have applied the proposed method to both single cell and bulk sequencing datasets for Epithelia to Mesenchymal Transition, a key process in cancer metastasis. The evaluation results show that our method significantly outperforms existing methods in finding miRNA-mRNA interactions in both single cell and bulk data. The results suggest that utilizing the pseudotemporal information from the data helps reveal the gene regulation in a biological process much better than using the static information. AVAILABILITY AND IMPLEMENTATION: R scripts and datasets can be found at https://github.com/AndresMCB/PTC. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: The development of new drugs is costly, time consuming and often accompanied with safety issues. Drug repurposing can avoid the expensive and lengthy process of drug development by finding new uses for already approved drugs. In order to repurpose drugs effectively, it is useful to know which proteins are targeted by which drugs. Computational models that estimate the interaction strength of new drug-target pairs have the potential to expedite drug repurposing. Several models have been proposed for this task. However, these models represent the drugs as strings, which is not a natural way to represent molecules. We propose a new model called GraphDTA that represents drugs as graphs and uses graph neural networks to predict drug-target affinity. We show that graph neural networks not only predict drug-target affinity better than non-deep learning models, but also outperform competing deep learning methods. Our results confirm that deep learning models are appropriate for drug-target binding affinity prediction, and that representing drugs as graphs can lead to further improvements. AVAILABILITY OF IMPLEMENTATION: The proposed models are implemented in Python. Related data, pre-trained models and source code are publicly available at https://github.com/thinng/GraphDTA. All scripts and data needed to reproduce the post hoc statistical analysis are available from https://doi.org/10.5281/zenodo.3603523. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Unravelling cancer driver genes is important in cancer research. Although computational methods have been developed to identify cancer drivers, most of them detect cancer drivers at population level. However, two patients who have the same cancer type and receive the same treatment may have different outcomes because each patient has a different genome and their disease might be driven by different driver genes. Therefore new methods are being developed for discovering cancer drivers at individual level, but existing personalized methods only focus on coding drivers while microRNAs (miRNAs) have been shown to drive cancer progression as well. Thus, novel methods are required to discover both coding and miRNA cancer drivers at individual level. RESULTS: We propose the novel method, pDriver, to discover personalized cancer drivers. pDriver includes two stages: (i) constructing gene networks for each cancer patient and (ii) discovering cancer drivers for each patient based on the constructed gene networks. To demonstrate the effectiveness of pDriver, we have applied it to five TCGA cancer datasets and compared it with the state-of-the-art methods. The result indicates that pDriver is more effective than other methods. Furthermore, pDriver can also detect miRNA cancer drivers and most of them have been confirmed to be associated with cancer by literature. We further analyze the predicted personalized drivers for breast cancer patients and the result shows that they are significantly enriched in many GO processes and KEGG pathways involved in breast cancer. AVAILABILITY AND IMPLEMENTATION: pDriver is available at https://github.com/pvvhoang/pDriver. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Accurate prognosis and identification of cancer subtypes at molecular level are important steps towards effective and personalised treatments of breast cancer. To this end, many computational methods have been developed to use gene (mRNA) expression data for breast cancer subtyping and prognosis. Meanwhile, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been extensively studied in the last 2 decades and their associations with breast cancer subtypes and prognosis have been evidenced. However, it is not clear whether using miRNA and/or lncRNA expression data helps improve the performance of gene expression based subtyping and prognosis methods, and this raises challenges as to how and when to use these data and methods in practice. RESULTS: In this paper, we conduct a comparative study of 35 methods, including 12 breast cancer subtyping methods and 23 breast cancer prognosis methods, on a collection of 19 independent breast cancer datasets. We aim to uncover the roles of miRNAs and lncRNAs in breast cancer subtyping and prognosis from the systematic comparison. In addition, we created an R package, CancerSubtypesPrognosis, including all the 35 methods to facilitate the reproducibility of the methods and streamline the evaluation. CONCLUSIONS: The experimental results show that integrating miRNA expression data helps improve the performance of the mRNA-based cancer subtyping methods. However, miRNA signatures are not as good as mRNA signatures for breast cancer prognosis. In general, lncRNA expression data does not help improve the mRNA-based methods in both cancer subtyping and cancer prognosis. These results suggest that the prognostic roles of miRNA/lncRNA signatures in the improvement of breast cancer prognosis needs to be further verified.

BACKGROUND: Existing computational methods for studying miRNA regulation are mostly based on bulk miRNA and mRNA expression data. However, bulk data only allows the analysis of miRNA regulation regarding a group of cells, rather than the miRNA regulation unique to individual cells. Recent advance in single-cell miRNA-mRNA co-sequencing technology has opened a way for investigating miRNA regulation at single-cell level. However, as currently single-cell miRNA-mRNA co-sequencing data is just emerging and only available at small-scale, there is a strong need of novel methods to exploit existing single-cell data for the study of cell-specific miRNA regulation. RESULTS: In this work, we propose a new method, CSmiR (Cell-Specific miRNA regulation) to combine single-cell miRNA-mRNA co-sequencing data and putative miRNA-mRNA binding information to identify miRNA regulatory networks at the resolution of individual cells. We apply CSmiR to the miRNA-mRNA co-sequencing data in 19 K562 single-cells to identify cell-specific miRNA-mRNA regulatory networks for understanding miRNA regulation in each K562 single-cell. By analyzing the obtained cell-specific miRNA-mRNA regulatory networks, we observe that the miRNA regulation in each K562 single-cell is unique. Moreover, we conduct detailed analysis on the cell-specific miRNA regulation associated with the miR-17/92 family as a case study. The comparison results indicate that CSmiR is effective in predicting cell-specific miRNA targets. Finally, through exploring cell-cell similarity matrix characterized by cell-specific miRNA regulation, CSmiR provides a novel strategy for clustering single-cells and helps to understand cell-cell crosstalk. CONCLUSIONS: To the best of our knowledge, CSmiR is the first method to explore miRNA regulation at a single-cell resolution level, and we believe that it can be a useful method to enhance the understanding of cell-specific miRNA regulation.

The classification of clinical samples based on gene expression data is an important part of precision medicine. In this manuscript, we show how transforming gene expression data into a set of personalized (sample-specific) networks can allow us to harness existing graph-based methods to improve classifier performance. Existing approaches to personalized gene networks have the limitation that they depend on other samples in the data and must get re-computed whenever a new sample is introduced. Here, we propose a novel method, called Personalized Annotation-based Networks (PAN), that avoids this limitation by using curated annotation databases to transform gene expression data into a graph. Unlike competing methods, PANs are calculated for each sample independent of the population, making it a more efficient way to obtain single-sample networks. Using three breast cancer datasets as a case study, we show that PAN classifiers not only predict cancer relapse better than gene features alone, but also outperform PPI (protein-protein interactions) and population-level graph-based classifiers. This work demonstrates the practical advantages of graph-based classification for high-dimensional genomic data, while offering a new approach to making sample-specific networks. Supplementary information: PAN and the baselines are implemented in Python. Source code and data are available at https://github.com/thinng/PAN.

In the disability employment service, an emerging challenge is to recommend the skills whose improvement will increase the employment perspective most. The process of a skill being improved is called an intervention and different skills are called factors. The problem involves recommendation for outcome improvement, which requires estimating the improvement in the employment perspective, i.e., the outcome, driven by interventions on recommended factors. Currently, most recommendation systems deployed for the employment service rely on traditional recommendation models where the desired outcome instead of the degree of outcome improvement is the main goal for optimization. In this paper, we present a causality-based approach for recommending factors for intervention to achieve the largest improvement in the employment potential of disabled job seekers. It involves inferring the causal effect of interventions on the employment outcome to make recommendations for individuals. The causal interpretation of our model can justify given recommendations. We conduct a case study with our industry partner in the disability employment service. Results show that the recommended interventions could improve the employability of disabled job seekers. Experiments are also carried out with datasets in other domains to demonstrate the promise of our approach in different applications.

This paper discusses the problem of causal query in observational data with hidden variables, with the aim of seeking the change of an outcome when "manipulating" a variable while given a set of plausible confounding variables which affect the manipulated variable and the outcome. Such an "experiment on data" to estimate the causal effect of the manipulated variable is useful for validating an experiment design using historical data or for exploring confounders when studying a new relationship. However, existing data-driven methods for causal effect estimation face some major challenges, including poor scalability with high dimensional data, low estimation accuracy due to heuristics used by the global causal structure learning algorithms, and the assumption of causal sufficiency when hidden variables are inevitable in data. In this paper, we develop theorems for using local search to find a superset of the adjustment (or confounding) variables for causal effect estimation from observational data under a realistic pretreatment assumption. The theorems ensure that the unbiased estimate of causal effect is included in the set of causal effects estimated by the superset of adjustment variables. Based on the developed theorems, we propose a data-driven algorithm for causal query. Experiments show that the proposed algorithm is faster and produces better causal effect estimation than an existing data-driven causal effect estimation method with hidden variables. The causal effects estimated by the proposed algorithm are as accurate as those by the state-of-the-art methods using domain knowledge.

MOTIVATION: Identifying cancer driver genes is a key task in cancer informatics. Most existing methods are focused on individual cancer drivers which regulate biological processes leading to cancer. However, the effect of a single gene may not be sufficient to drive cancer progression. Here, we hypothesize that there are driver gene groups that work in concert to regulate cancer, and we develop a novel computational method to detect those driver gene groups. RESULTS: We develop a novel method named DriverGroup to detect driver gene groups by using gene expression and gene interaction data. The proposed method has three stages: (i) constructing the gene network, (ii) discovering critical nodes of the constructed network and (iii) identifying driver gene groups based on the discovered critical nodes. Before evaluating the performance of DriverGroup in detecting cancer driver groups, we firstly assess its performance in detecting the influence of gene groups, a key step of DriverGroup. The application of DriverGroup to DREAM4 data demonstrates that it is more effective than other methods in detecting the regulation of gene groups. We then apply DriverGroup to the BRCA dataset to identify driver groups for breast cancer. The identified driver groups are promising as several group members are confirmed to be related to cancer in literature. We further use the predicted driver groups in survival analysis and the results show that the survival curves of patient subpopulations classified using the predicted driver groups are significantly differentiated, indicating the usefulness of DriverGroup. AVAILABILITY AND IMPLEMENTATION: DriverGroup is available at https://github.com/pvvhoang/DriverGroup. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

After publication of this supplement article [1], it was brought to our attention that the Fig. 3 was incorrect. The correct Fig. 3 is as below.

Causal feature selection has attracted much attention in recent years, as the causal features selected imply the causal mechanism related to the class attribute, leading to more reliable prediction models built using them. Currently there is a need of developing multi-source feature selection methods, since in many applications data for studying the same problem has been collected from various sources, such as multiple gene expression datasets obtained from different experiments for studying the causes of the same disease. However, the state-of-the-art causal feature selection methods generally tackle a single dataset, and a direct application of the methods to multiple datasets will result in unreliable results as the datasets may have different distributions. To address the challenges, by utilizing the concept of causal invariance in causal inference, we first formulate the problem of causal feature selection with multiple datasets as a search problem for an invariant set across the datasets, then give the upper and lower bounds of the invariant set, and finally we propose a new Multi-source Causal Feature Selection algorithm, MCFS. Using synthetic and real world datasets and 16 feature selection methods, the extensive experiments have validated the effectiveness of MCFS.

Breast cancer prognosis is challenging due to the heterogeneity of the disease. Various computational methods using bulk RNA-seq data have been proposed for breast cancer prognosis. However, these methods suffer from limited performances or ambiguous biological relevance, as a result of the neglect of intra-tumor heterogeneity. Recently, single cell RNA-sequencing (scRNA-seq) has emerged for studying tumor heterogeneity at cellular levels. In this paper, we propose a novel method, scPrognosis, to improve breast cancer prognosis with scRNA-seq data. scPrognosis uses the scRNA-seq data of the biological process Epithelial-to-Mesenchymal Transition (EMT). It firstly infers the EMT pseudotime and a dynamic gene co-expression network, then uses an integrative model to select genes important in EMT based on their expression variation and differentiation in different stages of EMT, and their roles in the dynamic gene co-expression network. To validate and apply the selected signatures to breast cancer prognosis, we use them as the features to build a prediction model with bulk RNA-seq data. The experimental results show that scPrognosis outperforms other benchmark breast cancer prognosis methods that use bulk RNA-seq data. Moreover, the dynamic changes in the expression of the selected signature genes in EMT may provide clues to the link between EMT and clinical outcomes of breast cancer. scPrognosis will also be useful when applied to scRNA-seq datasets of different biological processes other than EMT.

Until now, existing methods for identifying lncRNA related miRNA sponge modules mainly rely on lncRNA related miRNA sponge interaction networks, which may not provide a full picture of miRNA sponging activities in biological conditions. Hence there is a strong need of new computational methods to identify lncRNA related miRNA sponge modules. In this work, we propose a framework, LMSM, to identify LncRNA related MiRNA Sponge Modules from heterogeneous data. To understand the miRNA sponging activities in biological conditions, LMSM uses gene expression data to evaluate the influence of the shared miRNAs on the clustered sponge lncRNAs and mRNAs. We have applied LMSM to the human breast cancer (BRCA) dataset from The Cancer Genome Atlas (TCGA). As a result, we have found that the majority of LMSM modules are significantly implicated in BRCA and most of them are BRCA subtype-specific. Most of the mediating miRNAs act as crosslinks across different LMSM modules, and all of LMSM modules are statistically significant. Multi-label classification analysis shows that the performance of LMSM modules is significantly higher than baseline's performance, indicating the biological meanings of LMSM modules in classifying BRCA subtypes. The consistent results suggest that LMSM is robust in identifying lncRNA related miRNA sponge modules. Moreover, LMSM can be used to predict miRNA targets. Finally, LMSM outperforms a graph clustering-based strategy in identifying BRCA-related modules. Altogether, our study shows that LMSM is a promising method to investigate modular regulatory mechanism of sponge lncRNAs from heterogeneous data.

It is known that noncoding RNAs (ncRNAs) cover ∼98% of the transcriptome, but do not encode proteins. Among ncRNAs, long noncoding RNAs (lncRNAs) are a large and diverse class of RNA molecules, and are thought to be a gold mine of potential oncogenes, anti-oncogenes and new biomarkers. Although only a minority of lncRNAs is functionally characterized, it is clear that they are important regulators to modulate gene expression and involve in many biological functions. To reveal the functions and regulatory mechanisms of lncRNAs, it is vital to understand how lncRNAs regulate their target genes for implementing specific biological functions. In this article, we review the computational methods for inferring lncRNA-mRNA interactions and the third-party databases of storing lncRNA-mRNA regulatory relationships. We have found that the existing methods are based on statistical correlations between the gene expression levels of lncRNAs and mRNAs, and may not reveal gene regulatory relationships which are causal relationships. Moreover, these methods do not consider the modularity of lncRNA-mRNA regulatory networks, and thus, the networks identified are not module-specific. To address the above two issues, we propose a novel method, MSLCRN, to infer and analyze module-specific lncRNA-mRNA causal regulatory networks. We have applied it into glioblastoma multiforme, lung squamous cell carcinoma, ovarian cancer and prostate cancer, respectively. The experimental results show that MSLCRN, as an expression-based method, could be a useful complementary method to study lncRNA regulations.

BACKGROUND: microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and they play an important role in various biological processes in the human body. Therefore, identifying their regulation mechanisms is essential for the diagnostics and therapeutics for a wide range of diseases. There have been a large number of researches which use gene expression profiles to resolve this problem. However, the current methods have their own limitations. Some of them only identify the correlation of miRNA and mRNA expression levels instead of the causal or regulatory relationships while others infer the causality but with a high computational complexity. To overcome these issues, in this study, we propose a method to identify miRNA-mRNA regulatory relationships in breast cancer using the invariant causal prediction. The key idea of invariant causal prediction is that the cause miRNAs of their target mRNAs are the ones which have persistent causal relationships with the target mRNAs across different environments. RESULTS: In this research, we aim to find miRNA targets which are consistent across different breast cancer subtypes. Thus, first of all, we apply the Pam50 method to categorize BRCA samples into different "environment" groups based on different cancer subtypes. Then we use the invariant causal prediction method to find miRNA-mRNA regulatory relationships across subtypes. We validate the results with the miRNA-transfected experimental data and the results show that our method outperforms the state-of-the-art methods. In addition, we also integrate this new method with the Pearson correlation analysis method and Lasso in an ensemble method to take the advantages of these methods. We then validate the results of the ensemble method with the experimentally confirmed data and the ensemble method shows the best performance, even comparing to the proposed causal method. CONCLUSIONS: This research found miRNA targets which are consistent across different breast cancer subtypes. Further functional enrichment analysis shows that miRNAs involved in the regulatory relationships predicated by the proposed methods tend to synergistically regulate target genes, indicating the usefulness of these methods, and the identified miRNA targets could be used in the design of wet-lab experiments to discover the causes of breast cancer.

BACKGROUND: A microRNA (miRNA) sponge is an RNA molecule with multiple tandem miRNA response elements that can sequester miRNAs from their target mRNAs. Despite growing appreciation of the importance of miRNA sponges, our knowledge of their complex functions remains limited. Moreover, there is still a lack of miRNA sponge research tools that help researchers to quickly compare their proposed methods with other methods, apply existing methods to new datasets, or select appropriate methods for assisting in subsequent experimental design. RESULTS: To fill the gap, we present an R/Bioconductor package, miRspongeR, for simplifying the procedure of identifying and analyzing miRNA sponge interaction networks and modules. It provides seven popular methods and an integrative method to identify miRNA sponge interactions. Moreover, it supports the validation of miRNA sponge interactions and the identification of miRNA sponge modules, as well as functional enrichment and survival analysis of miRNA sponge modules. CONCLUSIONS: This package enables researchers to quickly evaluate their new methods, apply existing methods to new datasets, and consequently speed up miRNA sponge research.

BACKGROUND: Studying multiple microRNAs (miRNAs) synergism in gene regulation could help to understand the regulatory mechanisms of complicated human diseases caused by miRNAs. Several existing methods have been presented to infer miRNA synergism. Most of the current methods assume that miRNAs with shared targets at the sequence level are working synergistically. However, it is unclear if miRNAs with shared targets are working in concert to regulate the targets or they individually regulate the targets at different time points or different biological processes. A standard method to test the synergistic activities is to knock-down multiple miRNAs at the same time and measure the changes in the target genes. However, this approach may not be practical as we would have too many sets of miRNAs to test. RESULTS: n this paper, we present a novel framework called miRsyn for inferring miRNA synergism by using a causal inference method that mimics the multiple-intervention experiments, e.g. knocking-down multiple miRNAs, with observational data. Our results show that several miRNA-miRNA pairs that have shared targets at the sequence level are not working synergistically at the expression level. Moreover, the identified miRNA synergistic network is small-world and biologically meaningful, and a number of miRNA synergistic modules are significantly enriched in breast cancer. Our further analyses also reveal that most of synergistic miRNA-miRNA pairs show the same expression patterns. The comparison results indicate that the proposed multiple-intervention causal inference method performs better than the single-intervention causal inference method in identifying miRNA synergistic network. CONCLUSIONS: Taken together, the results imply that miRsyn is a promising framework for identifying miRNA synergism, and it could enhance the understanding of miRNA synergism in breast cancer.

With the increasing need of personalised decision making, such as personalised medicine and online recommendations, a growing attention has been paid to the discovery of the context and heterogeneity of causal relationships. Most existing methods, however, assume a known cause (e.g. a new drug) and focus on identifying from data the contexts of heterogeneous effects of the cause (e.g. patient groups with different responses to the new drug). There is no approach to efficiently detecting directly from observational data context specific causal relationships, i.e. discovering the causes and their contexts simultaneously. In this paper, by taking the advantages of highly efficient decision tree induction and the well established causal inference framework, we propose the Tree based Context Causal rule discovery (TCC) method, for efficient exploration of context specific causal relationships from data. Experiments with both synthetic and real world data sets show that TCC can effectively discover context specific causal rules from the data.

A key task in cancer genomics research is to identify cancer driver genes.As these genes initialise and progress cancer, understanding them is critical in designing effective cancer interventions.Although there are several methods developed to discover cancer drivers, most of them only identify coding drivers.However, non-coding RNAs can regulate driver mutations to develop cancer.Hence, novel methods are required to reveal both coding and non-coding cancer drivers.In this paper, we develop a novel framework named Controllability based Biological Network Analysis (CBNA) to uncover coding and non-coding cancer drivers (i.e.miRNA cancer drivers).CBNA integrates different genomic data types, including gene expression, gene network, mutation data, and contains a two-stage process: (1) Building a network for a condition (e.g.cancer condition) and (2) Identifying drivers.The application of CBNA to the BRCA dataset demonstrates that it is more effective than the existing methods in detecting coding cancer drivers.In addition, CBNA also predicts 17 miRNA drivers for breast cancer.Some of these predicted miRNA drivers have been validated by literature and the rest can be good candidates for wet-lab validation.We further use CBNA to detect subtype-specific cancer drivers and several predicted drivers have been confirmed to be related to breast cancer subtypes.Another application of CBNA is to discover epithelial-mesenchymal transition (EMT) drivers.Of the predicted EMT drivers, 7 coding and 6 miRNA drivers are in the known EMT gene lists. Author summaryCancer is a disease of cells in human body and it causes a high rate of deaths worldwide.There has been evidence that coding and non-coding RNAs are key players in the initialisation and progression of cancer.These coding and non-coding RNAs are considered as cancer drivers.To design better diagnostic and therapeutic plans for cancer patients, we need to know the roles of cancer drivers in cancer development as well as their regulatory

Discovering causal relationships from observational data is a crucial problem and it has applications in many research areas. The PC algorithm is the state-of-the-art constraint based method for causal discovery. However, runtime of the PC algorithm, in the worst-case, is exponential to the number of nodes (variables), and thus it is inefficient when being applied to high dimensional data, e.g., gene expression datasets. On another note, the advancement of computer hardware in the last decade has resulted in the widespread availability of multi-core personal computers. There is a significant motivation for designing a parallelized PC algorithm that is suitable for personal computers and does not require end users' parallel computing knowledge beyond their competency in using the PC algorithm. In this paper, we develop parallel-PC, a fast and memory efficient PC algorithm using the parallel computing technique. We apply our method to a range of synthetic and real-world high dimensional datasets. Experimental results on a dataset from the DREAM 5 challenge show that the original PC algorithm could not produce any results after running more than 24 hours; meanwhile, our parallel-PC algorithm managed to finish within around 12 hours with a 4-core CPU computer, and less than six hours with a 8-core CPU computer. Furthermore, we integrate parallel-PC into a causal inference method for inferring miRNA-mRNA regulatory relationships. The experimental results show that parallel-PC helps improve both the efficiency and accuracy of the causal inference algorithm.

Outliers are objects that are significantly different from the others in the same dataset. They often contain insightful information for understanding the data and the data generation process. Traditional outlier detection methods can generally be divided into two categories: model-based and proximity-based approaches. A new type of model-based approach has recently been proposed to use the Bayesian network (BN) framework to discover more meaningful outliers with better interpretability. They yield very good detection result when anomalousness is mainly due to the violation of the dependency among variables. However, when anomalousness is caused by reasons other than dependency violation, BN-based methods produce very poor performance. To address this problem, we propose an ensemble outlier detection method that combines BN-based and proximity-based techniques to achieve more stable outlier detection results in different scenarios. To our best knowledge, the proposed method is the first to bring together the two major categories of outlier detection techniques. Comprehensive experiments have been done on both synthetic and real world datasets, and the results show that our method outperforms the baseline methods in most cases.

Motivation: MicroRNAs (miRNAs) are small non-coding RNAs with the length of ∼22 nucleotides. miRNAs are involved in many biological processes including cancers. Recent studies show that long non-coding RNAs (lncRNAs) are emerging as miRNA sponges, playing important roles in cancer physiology and development. Despite accumulating appreciation of the importance of lncRNAs, the study of their complex functions is still in its preliminary stage. Based on the hypothesis of competing endogenous RNAs (ceRNAs), several computational methods have been proposed for investigating the competitive relationships between lncRNAs and miRNA target messenger RNAs (mRNAs). However, when the mRNAs are released from the control of miRNAs, it remains largely unknown as to how the sponge lncRNAs influence the expression levels of the endogenous miRNA targets. Results: We propose a novel method to construct lncRNA related miRNA sponge regulatory networks (LncmiRSRNs) by integrating matched lncRNA and mRNA expression profiles with clinical information and putative miRNA-target interactions. Using the method, we have constructed the LncmiRSRNs for four human cancers (glioblastoma multiforme, lung cancer, ovarian cancer and prostate cancer). Based on the networks, we discover that after being released from miRNA control, the target mRNAs are normally up-regulated by the sponge lncRNAs, and only a fraction of sponge lncRNA-mRNA regulatory relationships and hub lncRNAs are shared by the four cancers. Moreover, most sponge lncRNA-mRNA regulatory relationships show a rewired mode between different cancers, and a minority of sponge lncRNA-mRNA regulatory relationships conserved (appearing) in different cancers may act as a common pivot across cancers. Besides, differential and conserved hub lncRNAs may act as potential cancer drivers to influence the cancerous state in cancers. Functional enrichment and survival analysis indicate that the identified differential and conserved LncmiRSRN network modules work as functional units in biological processes, and can distinguish metastasis risks of cancers. Our analysis demonstrates the potential of integrating expression profiles, clinical information and miRNA-target interactions for investigating lncRNA regulatory mechanism. Availability and implementation: LncmiRSRN is freely available (https://github.com/zhangjunpeng411/LncmiRSRN). Supplementary information: Supplementary data are available at Bioinformatics online.

BACKGROUND: miRBase is the primary repository for published miRNA sequence and annotation data, and serves as the "go-to" place for miRNA research. However, the definition and annotation of miRNAs have been changed significantly across different versions of miRBase. The changes cause inconsistency in miRNA related data between different databases and articles published at different times. Several tools have been developed for different purposes of querying and converting the information of miRNAs between different miRBase versions, but none of them individually can provide the comprehensive information about miRNAs in miRBase and users will need to use a number of different tools in their analyses. RESULTS: We introduce miRBaseConverter, an R package integrating the latest miRBase version 22 available in Bioconductor to provide a suite of functions for converting and retrieving miRNA name (ID), accession, sequence, species, version and family information in different versions of miRBase. The package is implemented in R and available under the GPL-2 license from the Bioconductor website ( http://bioconductor.org/packages/miRBaseConverter/ ). A Shiny-based GUI suitable for non-R users is also available as a standalone application from the package and also as a web application at http://nugget.unisa.edu.au:3838/miRBaseConverter . miRBaseConverter has a built-in database for querying miRNA information in all species and for both pre-mature and mature miRNAs defined by miRBase. In addition, it is the first tool for batch querying the miRNA family information. The package aims to provide a comprehensive and easy-to-use tool for miRNA research community where researchers often utilize published miRNA data from different sources. CONCLUSIONS: The Bioconductor package miRBaseConverter and the Shiny-based web application are presented to provide a suite of functions for converting and retrieving miRNA name, accession, sequence, species, version and family information in different versions of miRBase. The package will serve a wide range of applications in miRNA research and could provide a full view of the miRNAs of interest.

BACKGROUND: Estimating heterogeneous treatment effect is a fundamental problem in biological and medical applications. Recently, several recursive partitioning methods have been proposed to identify the subgroups that respond differently towards a treatment, and they rely on a fitness criterion to minimize the error between the estimated treatment effects and the unobservable ground truths. RESULTS: In this paper, we propose that a heterogeneity criterion, which maximizes the differences of treatment effects among the subgroups, also needs to be considered. Moreover, we show that better performances can be achieved when the fitness and the heterogeneous criteria are considered simultaneously. Selecting the optimal splitting points then becomes a multi-objective problem; however, a solution that achieves optimal in both aspects are often not available. To solve this problem, we propose a multi-objective splitting procedure to balance both criteria. The proposed procedure is computationally efficient and fits naturally into the existing recursive partitioning framework. Experimental results show that the proposed multi-objective approach performs consistently better than existing ones. CONCLUSION: Heterogeneity should be considered with fitness in heterogeneous treatment effect estimation, and the proposed multi-objective splitting procedure achieves the best performance by balancing both criteria.

With more and more decisions being made by learnt algorithms from data, algorithmic discriminations have become a risk for civil rights. The detection of discrimination is a process of counterfactual reasoning. This paper proposes a general detection framework by combining a data mining method with a well established counterfactual reasoning framework, potential outcome model. The potential outcome model supports operational definitions of global and local discriminations and discriminations by combined factors, while a data mining method makes the detection efficient. The proposed method, instantiated by association rule mining with potential outcome model based causal effect estimation, is evaluated with four real world data sets and is compared with a Bayesian network (BN) based detection method. It is able to detect not only global discriminations that are detected by the BN based method, but also local and combined discriminations that the BN based method cannot find. The proposed method is efficient, and scales well with the data set size and the number of attributes.

Recent findings show that coding genes are not the only targets that miRNAs interact with. In fact, there is a pool of different RNAs competing with each other to attract miRNAs for interactions, thus acting as competing endogenous RNAs (ceRNAs). The ceRNAs indirectly regulate each other via the titration mechanism, i.e. the increasing concentration of a ceRNA will decrease the number of miRNAs that are available for interacting with other targets. The cross-talks between ceRNAs, i.e. their interactions mediated by miRNAs, have been identified as the drivers in many disease conditions, including cancers. In recent years, some computational methods have emerged for identifying ceRNA-ceRNA interactions. However, there remain great challenges and opportunities for developing computational methods to provide new insights into ceRNA regulatory mechanisms.In this paper, we review the publically available databases of ceRNA-ceRNA interactions and the computational methods for identifying ceRNA-ceRNA interactions (also known as miRNA sponge interactions). We also conduct a comparison study of the methods with a breast cancer dataset. Our aim is to provide a current snapshot of the advances of the computational methods in identifying miRNA sponge interactions and to discuss the remaining challenges.

SUMMARY: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. AVAILABILITY AND IMPLEMENTATION: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). CONTACT: [email protected] or [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Cancer is not a single disease and involves different subtypes characterized by different sets of molecules. Patients with different subtypes of cancer often react heterogeneously towards the same treatment. Currently, clinical diagnoses rather than molecular profiles are used to determine the most suitable treatment. A molecular level approach will allow a more precise and informed way for making treatment decisions, leading to a better survival chance and less suffering of patients. Although many computational methods have been proposed to identify cancer subtypes at molecular level, to the best of our knowledge none of them are designed to discover subtypes with heterogeneous treatment responses. RESULTS: In this article we propose the Survival Causal Tree (SCT) method. SCT is designed to discover patient subgroups with heterogeneous treatment effects from censored observational data. Results on TCGA breast invasive carcinoma and glioma datasets have shown that for each subtype identified by SCT, the patients treated with radiotherapy exhibit significantly different relapse free survival pattern when compared to patients without the treatment. With the capability to identify cancer subtypes with heterogeneous treatment responses, SCT is useful in helping to choose the most suitable treatment for individual patients. AVAILABILITY AND IMPLEMENTATION: Data and code are available at https://github.com/WeijiaZhang24/SurvivalCausalTree . CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: MicroRNA (miRNA) sponges with multiple tandem miRNA binding sequences can sequester miRNAs from their endogenous target mRNAs. Therefore, miRNA sponge acting as a decoy is extremely important for long-term loss-of-function studies both in vivo and in silico. Recently, a growing number of in silico methods have been used as an effective technique to generate hypotheses for in vivo methods for studying the biological functions and regulatory mechanisms of miRNA sponges. However, most existing in silico methods only focus on studying miRNA sponge interactions or networks in cancer, the module-level properties of miRNA sponges in cancer is still largely unknown. RESULTS: We propose a novel in silico method, called miRSM (miRNA Sponge Module) to infer miRNA sponge modules in breast cancer. We apply miRSM to the breast invasive carcinoma (BRCA) dataset provided by The Cancer Genome Altas (TCGA), and make functional validation of the computational results. We discover that most miRNA sponge interactions are module-conserved across two modules, and a minority of miRNA sponge interactions are module-specific, existing only in a single module. Through functional annotation and differential expression analysis, we also find that the modules discovered using miRSM are functional miRNA sponge modules associated with BRCA. Moreover, the module-specific miRNA sponge interactions among miRNA sponge modules may be involved in the progression and development of BRCA. Our experimental results show that miRSM is comparable to the benchmark methods in recovering experimentally confirmed miRNA sponge interactions, and miRSM outperforms the benchmark methods in identifying interactions that are related to breast cancer. CONCLUSIONS: Altogether, the functional validation results demonstrate that miRSM is a promising method to identify miRNA sponge modules and interactions, and may provide new insights for understanding the roles of miRNA sponges in cancer progression and development.

BACKGROUND: Recent studies have shown that the crosstalk between microRNA (miRNA) sponges plays an important role in human cancers. However, the co-regulation roles of miRNA sponges in protein-protein interactions (PPIs) are still unknown. RESULTS: In this study, we propose a multi-step method called miRSCoPPI to infer miRNA sponge co-regulation of PPIs. We focus on investigating breast cancer (BRCA) related miRNA sponge co-regulation, by integrating heterogeneous data, including miRNA, long non-coding RNA (lncRNA) and messenger RNA (mRNA) expression data, experimentally validated miRNA-target interactions, PPIs and lncRNA-target interactions, and the list of breast cancer genes. We find that the inferred BRCA-related miRSCoPPI network is highly connected and scale free. The top 10% hub genes in the BRCA-related miRSCoPPI network have potential biological implications in breast cancer. By utilizing a graph clustering method, we discover 17 BRCA-related miRSCoPPI modules. Through pathway enrichment analysis of the modules, we find that several modules are significantly enriched in pathways associated with breast cancer. Moreover, 10 modules have good performance in classifying breast tumor and normal samples, and can act as module signatures for prognostication. By using putative computationally predicted miRNA-target interactions, we have consistent results with those obtained using experimentally validated miRNA-target interactions, indicating that miRSCoPPI is robust in inferring miRNA sponge co-regulation of PPIs in human breast cancer. CONCLUSIONS: Taken together, the results demonstrate that miRSCoPPI is a promising tool for inferring BRCA-related miRNA sponge co-regulation of PPIs and it can help with the understanding of the co-regulation roles of miRNA sponges on the PPIs.

Uncovering causal relationships in data is a major objective of data analytics. Currently, there is a need for scalable and automated methods for causal relationship exploration in data. Classification methods are fast and they could be practical substitutes for finding causal signals in data. However, classification methods are not designed for causal discovery and a classification method may find false causal signals and miss the true ones. In this paper, we develop a causal decision tree (CDT) where nodes have causal interpretations. Our method follows a well-established causal inference framework and makes use of a classic statistical test to establish the causal relationship between a predictor variable and the outcome variable. At the same time, by taking the advantages of normal decision trees, a CDT provides a compact graphical representation of the causal relationships, and the construction of a CDT is fast as a result of the divide and conquer strategy employed, making CDTs practical for representing and finding causal signals in large data sets. Experiment results demonstrate that CDTs can identify meaningful causal relationships and the CDT algorithm is scalable.

Cross-view data are collected from two different views or sources about the same subjects. As the information from these views often consolidate and/or complement each other, cross-view data analysis can gain more insights for decision making. A main challenge of cross-view data analysis is how to effectively explore the inherently correlated and high-dimensional data. Dimension reduction offers an effective solution for this problem. However, how to choose right models and parameters involved for dimension reduction is still an open problem. In this paper, we propose an effective sparse learning algorithm for cross-view dimensionality reduction. A distinguished character of our model selection is that it is nonparametric and automatic. Specifically, we represent the correlation of cross-view data using a covariance matrix. Then, we decompose the matrix into a sequence of low-rank ones by solving an optimization problem in an alternating least squares manner. More importantly, a new and nonparametric sparsity-inducing function is developed to derive a parsimonious model. Extensive experiments are conducted on real-world data sets to evaluate the effectiveness of the proposed algorithm. The results show that our method is competitive with the state-of-the-art sparse learning algorithms.

Randomised controlled trials (RCTs) are the most effective approach to causal discovery, but in many circumstances it is impossible to conduct RCTs. Therefore, observational studies based on passively observed data are widely accepted as an alternative to RCTs. However, in observational studies, prior knowledge is required to generate the hypotheses about the cause-effect relationships to be tested, and hence they can only be applied to problems with available domain knowledge and a handful of variables. In practice, many datasets are of high dimensionality, which leaves observational studies out of the opportunities for causal discovery from such a wealth of data sources. In another direction, many efficient data mining methods have been developed to identify associations among variables in large datasets. The problem is that causal relationships imply associations, but the reverse is not always true. However, we can see the synergy between the two paradigms here. Specifically, association rule mining can be used to deal with the high-dimensionality problem, whereas observational studies can be utilised to eliminate noncausal associations. In this article, we propose the concept of causal rules (CRs) and develop an algorithm for mining CRs in large datasets. We use the idea of retrospective cohort studies to detect CRs based on the results of association rule mining. Experiments with both synthetic and real-world datasets have demonstrated the effectiveness and efficiency of CR mining. In comparison with the commonly used causal discovery methods, the proposed approach generally is faster and has better or competitive performance in finding correct or sensible causes. It is also capable of finding a cause consisting of multiple variables—a feature that other causal discovery methods do not possess.

microRNAs (miRNAs) are important gene regulators. They control a wide range of biological processes and are involved in several types of cancers. Thus, exploring miRNA functions is important for diagnostics and therapeutics. To date, there are few feasible experimental techniques for discovering miRNA regulatory mechanisms. Alternatively, predictions of miRNA-mRNA regulatory relationships by computational methods have increasingly achieved promising results. Computational approaches are proving their ability as effective tools in reducing the number of biological experiments that must be conducted and to assist with the design of the experiments. In this review, we categorize and review different computational approaches to identify miRNA activities and functions, including the co-regulation of miRNAs and transcription factors. Our main focuses are on the recent approaches that use multiple data types for exploring miRNA functions. We discuss the remaining challenges in the evaluation and selection of models based on the results from a case study. Finally, we analyse the remaining challenges of each computational approach and suggest some future research directions.

MOTIVATION: MicroRNAs (miRNAs) play crucial roles in complex cellular networks by binding to the messenger RNAs (mRNAs) of protein coding genes. It has been found that miRNA regulation is often condition-specific. A number of computational approaches have been developed to identify miRNA activity specific to a condition of interest using gene expression data. However, most of the methods only use the data in a single condition, and thus, the activity discovered may not be unique to the condition of interest. Additionally, these methods are based on statistical associations between the gene expression levels of miRNAs and mRNAs, so they may not be able to reveal real gene regulatory relationships, which are causal relationships. RESULTS: We propose a novel method to infer condition-specific miRNA activity by considering (i) the difference between the regulatory behavior that an miRNA has in the condition of interest and its behavior in the other conditions; (ii) the causal semantics of miRNA-mRNA relationships. The method is applied to the epithelial-mesenchymal transition (EMT) and multi-class cancer (MCC) datasets. The validation by the results of transfection experiments shows that our approach is effective in discovering significant miRNA-mRNA interactions. Functional and pathway analysis and literature validation indicate that the identified active miRNAs are closely associated with the specific biological processes, diseases and pathways. More detailed analysis of the activity of the active miRNAs implies that some active miRNAs show different regulation types in different conditions, but some have the same regulation types and their activity only differs in different conditions in the strengths of regulation. AVAILABILITY AND IMPLEMENTATION: The R and Matlab scripts are in the Supplementary materials.

MOTIVATION: microRNAs (miRNAs) are known to play an essential role in the post-transcriptional gene regulation in plants and animals. Currently, several computational approaches have been developed with a shared aim to elucidate miRNA-mRNA regulatory relationships. Although these existing computational methods discover the statistical relationships, such as correlations and associations between miRNAs and mRNAs at data level, such statistical relationships are not necessarily the real causal regulatory relationships that would ultimately provide useful insights into the causes of gene regulations. The standard method for determining causal relationships is randomized controlled perturbation experiments. In practice, however, such experiments are expensive and time consuming. Our motivation for this study is to discover the miRNA-mRNA causal regulatory relationships from observational data. RESULTS: We present a causality discovery-based method to uncover the causal regulatory relationship between miRNAs and mRNAs, using expression profiles of miRNAs and mRNAs without taking into consideration the previous target information. We apply this method to the epithelial-to-mesenchymal transition (EMT) datasets and validate the computational discoveries by a controlled biological experiment for the miR-200 family. A significant portion of the regulatory relationships discovered in data is consistent with those identified by experiments. In addition, the top genes that are causally regulated by miRNAs are highly relevant to the biological conditions of the datasets. The results indicate that the causal discovery method effectively discovers miRNA regulatory relationships in data. Although computational predictions may not completely replace intervention experiments, the accurate and reliable discoveries in data are cost effective for the design of miRNA experiments and the understanding of miRNA-mRNA regulatory relationships.

BACKGROUND: Transcription factors (TFs) and microRNAs (miRNAs) are primary metazoan gene regulators. Regulatory mechanisms of the two main regulators are of great interest to biologists and may provide insights into the causes of diseases. However, the interplay between miRNAs and TFs in a regulatory network still remains unearthed. Currently, it is very difficult to study the regulatory mechanisms that involve both miRNAs and TFs in a biological lab. Even at data level, a network involving miRNAs, TFs and genes will be too complicated to achieve. Previous research has been mostly directed at inferring either miRNA or TF regulatory networks from data. However, networks involving a single type of regulator may not fully reveal the complex gene regulatory mechanisms, for instance, the way in which a TF indirectly regulates a gene via a miRNA. RESULTS: We propose a framework to learn from heterogeneous data the three-component regulatory networks, with the presence of miRNAs, TFs, and mRNAs. This method firstly utilises Bayesian network structure learning to construct a regulatory network from multiple sources of data: gene expression profiles of miRNAs, TFs and mRNAs, target information based on sequence data, and sample categories. Then, in order to produce more meaningful results for further biological experimentation and research, the method searches the learnt network to identify the interplay between miRNAs and TFs and applies a network motif finding algorithm to further infer the network.We apply the proposed framework to the data sets of epithelial-to-mesenchymal transition (EMT). The results elucidate the complex gene regulatory mechanism for EMT which involves both TFs and miRNAs. Several discovered interactions and molecular functions have been confirmed by literature. In addition, many other discovered interactions and bio-markers are of high statistical significance and thus can be good candidates for validation by experiments. Moreover, the results generated by our method are compact, involving a small number of interactions which have been proved highly relevant to EMT. CONCLUSIONS: We have designed a framework to infer gene regulatory networks involving both TFs and miRNAs from multiple sources of data, including gene expression data, target information, and sample categories. Results on the EMT data sets have shown that the proposed approach is able to produce compact and meaningful gene regulatory networks that are highly relevant to the biological conditions of the data sets. This framework has the potential for application to other heterogeneous datasets to reveal the complex gene regulatory relationships.

Discovering causal relationships in large databases of observational data is challenging. The pioneering work in this area was rooted in the theory of Bayesian network (BN) learning, which however, is a NP-complete problem. Hence several constraint-based algorithms have been developed to efficiently discover causations in large databases. These methods usually use the idea of BN learning, directly or indirectly, and are focused on causal relationships with single cause variables. In this paper, we propose an approach to mine causal rules in large databases of binary variables. Our method expands the scope of causality discovery to causal relationships with multiple cause variables, and we utilise partial association tests to exclude noncausal associations, to ensure the high reliability of discovered causal rules. Furthermore an efficient algorithm is designed for the tests in large databases. We assess the method with a set of real-world diagnostic data. The results show that our method can effectively discover interesting causal rules in large databases.