Aristotle: stratified causal discovery for omics data

Background There has been a simultaneous increase in demand and accessibility across genomics, transcriptomics, proteomics and metabolomics data, known as omics data. This has encouraged widespread application of omics data in life sciences, from personalized medicine to the discovery of underlying pathophysiology of diseases. Causal analysis of omics data may provide important insight into the underlying biological mechanisms. Existing causal analysis methods yield promising results when identifying potential general causes of an observed outcome based on omics data. However, they may fail to discover the causes specific to a particular stratum of individuals and missing from others. Methods To fill this gap, we introduce the problem of stratified causal discovery and propose a method, Aristotle, for solving it. Aristotle addresses the two challenges intrinsic to omics data: high dimensionality and hidden stratification. It employs existing biological knowledge and a state-of-the-art patient stratification method to tackle the above challenges and applies a quasi-experimental design method to each stratum to find stratum-specific potential causes. Results Evaluation based on synthetic data shows better performance for Aristotle in discovering true causes under different conditions compared to existing causal discovery methods. Experiments on a real dataset on Anthracycline Cardiotoxicity indicate that Aristotle’s predictions are consistent with the existing literature. Moreover, Aristotle makes additional predictions that suggest further investigations.

Causal Discovery in Manufacturing: A Structured Literature Review

Industry 4.0 radically alters manufacturing organization and management, fostering collection and analysis of increasing amounts of data. Advanced data analytics, such as machine learning (ML), are essential for implementing Industry 4.0 and obtaining insights regarding production, better decision support, and enhanced manufacturing quality and sustainability. ML outperforms traditional approaches in many cases, but its complexity leads to unclear bases for decisions. Thus, acceptance of ML and, concomitantly, Industry 4.0, is hindered due to increasing requirements of fairness, accountability, and transparency, especially in sensitive-use cases. ML does not augment organizational knowledge, which is highly desired by manufacturing experts. Causal discovery promises a solution by providing insights on causal relationships that go beyond traditional ML’s statistical dependency. Causal discovery has a theoretical background and been successfully applied in medicine, genetics, and ecology. However, in manufacturing, only experimental and scattered applications are known; no comprehensive overview about how causal discovery can be applied in manufacturing is available. This paper investigates the state and development of research on causal discovery in manufacturing by focusing on motivations for application, common application scenarios and approaches, impacts, and implementation challenges. Based on the structured literature review, four core areas are identified, and a research agenda is proposed.

Causal Discovery with Confounding Cascade Nonlinear Additive Noise Models

Identification of causal direction between a causal-effect pair from observed data has recently attracted much attention. Various methods based on functional causal models have been proposed to solve this problem, by assuming the causal process satisfies some (structural) constraints and showing that the reverse direction violates such constraints. The nonlinear additive noise model has been demonstrated to be effective for this purpose, but the model class does not allow any confounding or intermediate variables between a cause pair–even if each direct causal relation follows this model. However, omitting the latent causal variables is frequently encountered in practice. After the omission, the model does not necessarily follow the model constraints. As a consequence, the nonlinear additive noise model may fail to correctly discover causal direction. In this work, we propose a confounding cascade nonlinear additive noise model to represent such causal influences–each direct causal relation follows the nonlinear additive noise model but we observe only the initial cause and final effect. We further propose a method to estimate the model, including the unmeasured confounding and intermediate variables, from data under the variational auto-encoder framework. Our theoretical results show that with our model, the causal direction is identifiable under suitable technical conditions on the data generation process. Simulation results illustrate the power of the proposed method in identifying indirect causal relations across various settings, and experimental results on real data suggest that the proposed model and method greatly extend the applicability of causal discovery based on functional causal models in nonlinear cases.

Could Causal Discovery in Proteogenomics Assist in Understanding Gene–Protein Relations? A Perennial Fruit Tree Case Study Using Sweet Cherry as a Model

Genome-wide transcriptome analysis is a method that produces important data on plant biology at a systemic level. The lack of understanding of the relationships between proteins and genes in plants necessitates a further thorough analysis at the proteogenomic level. Recently, our group generated a quantitative proteogenomic atlas of 15 sweet cherry (Prunus avium L.) cv. ‘Tragana Edessis’ tissues represented by 29,247 genes and 7584 proteins. The aim of the current study was to perform a targeted analysis at the gene/protein level to assess the structure of their relation, and the biological implications. Weighted correlation network analysis and causal modeling were employed to, respectively, cluster the gene/protein pairs, and reveal their cause–effect relations, aiming to assess the associated biological functions. To the best of our knowledge, this is the first time that causal modeling has been employed within the proteogenomics concept in plants. The analysis revealed the complex nature of causal relations among genes/proteins that are important for traits of interest in perennial fruit trees, particularly regarding the fruit softening and ripening process in sweet cherry. Causal discovery could be used to highlight persistent relations at the gene/protein level, stimulating biological interpretation and facilitating further study of the proteogenomic atlas in plants.

Causal Discovery in High-Dimensional Point Process Networks with Hidden Nodes

Thanks to technological advances leading to near-continuous time observations, emerging multivariate point process data offer new opportunities for causal discovery. However, a key obstacle in achieving this goal is that many relevant processes may not be observed in practice. Naïve estimation approaches that ignore these hidden variables can generate misleading results because of the unadjusted confounding. To plug this gap, we propose a deconfounding procedure to estimate high-dimensional point process networks with only a subset of the nodes being observed. Our method allows flexible connections between the observed and unobserved processes. It also allows the number of unobserved processes to be unknown and potentially larger than the number of observed nodes. Theoretical analyses and numerical studies highlight the advantages of the proposed method in identifying causal interactions among the observed processes.