Integrated causal inference modeling uncovers novel causal factors and potential therapeutic targets of Qingjin Yiqi granules for chronic fatigue syndrome

Objective:Chronic fatigue syndrome(CFS)is a prevalent symptom of post-coronavirus disease 2019(COVID-19)and is associated with unclear disease mechanisms.The herbal medicine Qingjin Yiqi granules(QJYQ)constitute a clinically approved formula for treating post-COVID-19;however,its potential as a drug target for treating CFS remains largely unknown.This study aimed to identify novel causal factors for CFS and elucidate the potential targets and pharmacological mechanisms of action of QJYQ in treating CFS.Methods:This prospective cohort analysis included 4,212 adults aged≥65 years who were followed up for 7 years with 435 incident CFS cases.Causal modeling and multivariate logistic regression analysis were performed to identify the potential causal determinants of CFS.A proteome-wide,two-sample Mendelian randomization(MR)analysis was employed to explore the proteins associated with the identified causal factors of CFS,which may serve as potential drug targets.Furthermore,we performed a virtual screening analysis to assess the binding affinity between the bioactive compounds in QJYQ and CFS-associated proteins.Results:Among 4,212 participants(47.5%men)with a median age of 69 years(interquartile range:69–70 years)enrolled in 2004,435 developed CFS by 2011.Causal graph analysis with multivariate logistic regression identified frequent cough(odds ratio:1.74,95%confidence interval[CI]:1.15–2.63)and insomnia(odds ratio:2.59,95%CI:1.77–3.79)as novel causal factors of CFS.Proteome-wide MR analysis revealed that the upregulation of endothelial cell-selective adhesion molecule(ESAM)was causally linked to both chronic cough(odds ratio:1.019,95%CI:1.012–1.026,P=2.75 e^(−05))and insomnia(odds ratio:1.015,95%CI:1.008–1.022,P=4.40 e^(−08))in CFS.The major bioactive compounds of QJYQ,ginsenoside Rb2(docking score:−6.03)and RG4(docking score:−6.15),bound to ESAM with high affinity based on virtual screening.Conclusions:Our integrated analytical framework combining epidemiological,genetic,and in silico data provides a novel strategy for elucidating complex disease mechanisms,such as CFS,and informing models of action of traditional Chinese medicines,such as QJYQ.Further validation in animal models is warranted to confirm the potential pharmacological effects of QJYQ on ESAM and as a treatment for CFS.

Causal role of immune cells in obstructive sleep apnea hypopnea syndrome:Mendelian randomization study

BACKGROUND Despite being one of the most prevalent sleep disorders,obstructive sleep apnea hypoventilation syndrome(OSAHS)has limited information on its immunologic foundation.The immunological underpinnings of certain major psychiatric diseases have been uncovered in recent years thanks to the extensive use of genome-wide association studies(GWAS)and genotyping techniques using highdensity genetic markers(e.g.,SNP or CNVs).But this tactic hasn't yet been applied to OSAHS.Using a Mendelian randomization analysis,we analyzed the causal link between immune cells and the illness in order to comprehend the immunological bases of OSAHS.AIM To investigate the immune cells'association with OSAHS via genetic methods,guiding future clinical research.METHODS A comprehensive two-sample mendelian randomization study was conducted to investigate the causal relationship between immune cell characteristics and OSAHS.Summary statistics for each immune cell feature were obtained from the GWAS catalog.Information on 731 immune cell properties,such as morphologic parameters,median fluorescence intensity,absolute cellular,and relative cellular,was compiled using publicly available genetic databases.The results'robustness,heterogeneity,and horizontal pleiotropy were confirmed using extensive sensitivity examination.RESULTS Following false discovery rate(FDR)correction,no statistically significant effect of OSAHS on immunophenotypes was observed.However,two lymphocyte subsets were found to have a significant association with the risk of OSAHS:Basophil%CD33dim HLA DR-CD66b-(OR=1.03,95%CI=1.01-1.03,P<0.001);CD38 on IgD+CD24-B cell(OR=1.04,95%CI=1.02-1.04,P=0.019).CONCLUSION This study shows a strong link between immune cells and OSAHS through a gene approach,thus offering direction for potential future medical research.

Immune cell signatures and causal association with irritable bowel syndrome:A mendelian randomization study

BACKGROUND The mucosal barrier's immune-brain interactions,pivotal for neural development and function,are increasingly recognized for their potential causal and therapeutic relevance to irritable bowel syndrome(IBS).Prior studies linking immune inflammation with IBS have been inconsistent.To further elucidate this relationship,we conducted a Mendelian randomization(MR)analysis of 731 immune cell markers to dissect the influence of various immune phenotypes on IBS.Our goal was to deepen our understanding of the disrupted brain-gut axis in IBS and to identify novel therapeutic targets.AIM To leverage publicly available data to perform MR analysis on 731 immune cell markers and explore their impact on IBS.We aimed to uncover immunophenotypic associations with IBS that could inform future drug development and therapeutic strategies.METHODS We performed a comprehensive two-sample MR analysis to evaluate the causal relationship between immune cell markers and IBS.By utilizing genetic data from public databases,we examined the causal associations between 731 immune cell markers,encompassing median fluorescence intensity,relative cell abundance,absolute cell count,and morphological parameters,with IBS susceptibility.Sensitivity analyses were conducted to validate our findings and address potential heterogeneity and pleiotropy.RESULTS Bidirectional false discovery rate correction indicated no significant influence of IBS on immunophenotypes.However,our analysis revealed a causal impact of IBS on 30 out of 731 immune phenotypes(P<0.05).Nine immune phenotypes demonstrated a protective effect against IBS[inverse variance weighting(IVW)<0.05,odd ratio(OR)<1],while 21 others were associated with an increased risk of IBS onset(IVW≥0.05,OR≥1).CONCLUSION Our findings underscore a substantial genetic correlation between immune cell phenotypes and IBS,providing valuable insights into the pathophysiology of the condition.These results pave the way for the development of more precise biomarkers and targeted therapies for IBS.Furthermore,this research enriches our comprehension of immune cell roles in IBS pathogenesis,offering a foundation for more effective,personalized treatment approaches.These advancements hold promise for improving IBS patient quality of life and reducing the disease burden on individuals and their families.

基于Partial New Causality的因果脑网络情绪识别

为了研究情绪产生过程中脑区以及通道之间的因果作用,在部分格兰杰与新型因果关系的基础上,提出一种用于研究时间序列之间因果关系的部分新型因果关系(PNC)方法。在不同情绪下选取脑区内的8个通道,用PNC计算脑区内通道之间的因果连接关系,根据连接关系构建因果网络;对因果网络中节点的信息流向和介数属性进行分析,将PNC因果网络和Granger因果网络节点之间的因果连接视为一种特征送入SVM中训练分类。实验结果表明,基于PNC因果网络和Granger因果网络的平均识别精度分别为76.4%和68.5%,PNC可用于计算时间序列之间的因果关系。

Causal temporal graph attention network for fault diagnosis of chemical processes

Fault detection and diagnosis(FDD)plays a significant role in ensuring the safety and stability of chemical processes.With the development of artificial intelligence(AI)and big data technologies,data-driven approaches with excellent performance are widely used for FDD in chemical processes.However,improved predictive accuracy has often been achieved through increased model complexity,which turns models into black-box methods and causes uncertainty regarding their decisions.In this study,a causal temporal graph attention network(CTGAN)is proposed for fault diagnosis of chemical processes.A chemical causal graph is built by causal inference to represent the propagation path of faults.The attention mechanism and chemical causal graph were combined to help us notice the key variables relating to fault fluctuations.Experiments in the Tennessee Eastman(TE)process and the green ammonia(GA)process showed that CTGAN achieved high performance and good explainability.

Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

TCAS-PINN:Physics-informed neural networks with a novel temporal causality-based adaptive sampling method

Physics-informed neural networks(PINNs)have become an attractive machine learning framework for obtaining solutions to partial differential equations(PDEs).PINNs embed initial,boundary,and PDE constraints into the loss function.The performance of PINNs is generally affected by both training and sampling.Specifically,training methods focus on how to overcome the training difficulties caused by the special PDE residual loss of PINNs,and sampling methods are concerned with the location and distribution of the sampling points upon which evaluations of PDE residual loss are accomplished.However,a common problem among these original PINNs is that they omit special temporal information utilization during the training or sampling stages when dealing with an important PDE category,namely,time-dependent PDEs,where temporal information plays a key role in the algorithms used.There is one method,called Causal PINN,that considers temporal causality at the training level but not special temporal utilization at the sampling level.Incorporating temporal knowledge into sampling remains to be studied.To fill this gap,we propose a novel temporal causality-based adaptive sampling method that dynamically determines the sampling ratio according to both PDE residual and temporal causality.By designing a sampling ratio determined by both residual loss and temporal causality to control the number and location of sampled points in each temporal sub-domain,we provide a practical solution by incorporating temporal information into sampling.Numerical experiments of several nonlinear time-dependent PDEs,including the Cahn–Hilliard,Korteweg–de Vries,Allen–Cahn and wave equations,show that our proposed sampling method can improve the performance.We demonstrate that using such a relatively simple sampling method can improve prediction performance by up to two orders of magnitude compared with the results from other methods,especially when points are limited.

Effects of Three-Baryon Forces Constrained by Causality Condition on the Equation of State with Kaon Condensation

Possibility of kaon-condensed phase in hyperon-mixed matter is considered as high-density multistrangeness system,which may be realized in neutron stars.The interaction model is based on chiral symmetry for kaon-baryon and kaon-kaon interactions,being combined with the relativistic mean-field theory for two-body baryonbaryon(B-B)interaction.In addition,the Lorentz invariant forms of many-baryon repulsive force(MBR)and threenucleon attractive force(TNA)are phenomenologically introduced,where unknown parameters are fixed to satisfy the saturation properties of symmetric nuclear matter and the causality condition that the sound velocity should be less than the speed of light.It is shown that the equation of state with kaon condensation in hyperon-mixed matter is stiff enough to be consistent with recent observations of massive neutron stars.

Causal association between 25-hydroxyvitamin D status and cataract development:A two-sample Mendelian randomization study

BACKGROUND Vitamin deficiencies are linked to various eye diseases,and the influence of vitamin D on cataract formation has been noted in prior research.However,detailed investigations into the causal relationship between 25-(OH)D status and cataract development remain scarce.AIM To explore a possible causal link between cataracts and vitamin D.METHODS In this study,we explored the causal link between 25-(OH)D levels and cataract development using Mendelian randomization.Our analytical approach included inverse-variance weighting(IVW),MR-Egger,weighted median,simple mode,and weighted mode methods.The primary analyses utilized IVW with random effects,supplemented by sensitivity and heterogeneity tests using both IVW and MR-Egger.MR-Egger was also applied for pleiotropy testing.Additionally,a leave-one-out analysis helped identify potentially impactful single-nucleotide polymorphisms.RESULTS The analysis revealed a positive association between 25-(OH)D levels and the risk of developing cataracts(OR=1.11,95%CI:1.00-1.22;P=0.032).The heterogeneity test revealed that our IVW analysis exhibited minimal heterogeneity(P>0.05),and the pleiotropy test findings confirmed the absence of pleiotropy within our IVW analysis(P>0.05).Furthermore,a search of the human genotype-phenotype association database failed to identify any potentially relevant risk-factor single nucleotide polymorphisms.CONCLUSION There is a potential causal link between 25-(OH)D levels and the development of cataracts,suggesting that greater 25-(OH)D levels may be a contributing risk factor for cataract formation.Further experimental research is required to confirm these findings.

Causal association between 731 immunocyte phenotypes and liver cirrhosis: A bidirectional two-sample mendelian randomization analysis

BACKGROUND Liver cirrhosis is a progressive hepatic disease whose immunological basis has attracted increasing attention.However,it remains unclear whether a concrete causal association exists between immunocyte phenotypes and liver cirrhosis.AIM To explore the concrete causal relationships between immunocyte phenotypes and liver cirrhosis through a mendelian randomization(MR)study.METHODS Data on 731 immunocyte phenotypes were obtained from genome-wide assoc-iation studies.Liver cirrhosis data were derived from the Finn Gen dataset,which included 214403 individuals of European ancestry.We used inverse variable weighting as the primary analysis method to assess the causal relationship.Sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy.RESULTS The MR analysis demonstrated that 11 immune cell phenotypes have a positive association with liver cirrhosis[P<0.05,odds ratio(OR)>1]and that 9 immu-nocyte phenotypes were negatively correlated with liver cirrhosis(P<0.05,OR<1).Liver cirrhosis was positively linked to 9 immune cell phenotypes(P<0.05,OR>1)and negatively linked to 10 immune cell phenotypes(P<0.05;OR<1).None of these associations showed heterogeneity or horizontally pleiotropy(P>0.05).CONCLUSION This bidirectional two-sample MR study demonstrated a concrete causal association between immunocyte phenotypes and liver cirrhosis.These findings offer new directions for the treatment of liver cirrhosis.

Noncausal relationship between body weight and breast cancer based on bidirectional Mendelian randomization evidence

Background:Some observational associations between body weight and breast cancer have attracted attention.However,the causal relationship between these 2 factors remains unclear,and more clinical outcomes are needed for its validation.Methods:Based on statistical data from a Genome Wide Association Study,we performed a bidirectional Mendelian randomization analysis to assess the bidirectional causal relationship between body weight and breast cancer using 4 methods,with inverse variance weighting as the primarymethod.To verify the robustness and reliability of the causal relationship,we performed a sensitivity analysis using horizontal pleiotropy,outlier,and one-by-one elimination tests.Results:The inverse variance weighting results revealed no significant positive causal relationship between body weight and breast cancer.Similarly,the reverse analysis revealed no causal effect of breast cancer on body weight.Conclusions:The relationship between body weight and breast cancer may be attributed to confounding factors.

Mendelian Randomization Study of Causal Relationship between Inflammatory Factors and Vascular Dementia and Chinese Herbal Medicines Screening for Prevention and Treatment

Objective: This study aims to examine the causal relationship between inflammatory factors and the probability of developing vascular dementia (VD) using Mendelian Randomization (MR) and Chinese herbal medicine prediction method, and to screen potential Chinese herbal medicines for the prevention and treatment of VD. Methods: Single nucleotide polymorphisms (SNPs) that exhibit a strong association with vascular dementia (VD) were identified as instrumental variables from the summary statistics of genome-wide association studies (GWAS). The primary analytical method employed was inverse variance weighting (IVW), while auxiliary analyses included the MR-Egger method, weighted median method, simple model, and weighted model. A two-way Mendelian randomization analysis was conducted to assess the causal relationship between inflammatory factors and the risk of VD, thereby identifying the key inflammatory factors involved. The MR-Egger intercept test and Cochran’s Q test were employed to assess the horizontal polymorphism and heterogeneity of instrumental variables. A sensitivity analysis was conducted by excluding one method at a time. Ultimately, based on key inflammatory factors, predictions for the prevention and treatment using traditional Chinese medicine were made, along with the screening of homologous herbal remedies. Results: Based on the results of the forward MR, the probability of developing VD was elevated when the inflammatory factors CXCL10 and CXCL5 were expressed at higher levels, whereas the probability of developing VD decreased as the expression levels of IL-13 and IL-20RA increased. These findings were supported by the assessment of pleiotropy, heterogeneity, and sensitivity. The results of the reverse MR analysis showed that there was no causal relationship between VD, as an exposure dataset, and these four inflammatory factors. According to the key inflammatory factors, 37 Chinese herbal medicines such as Siraitia grosvenorii were selected. Their characteristics including four natures, five flavors, channel tropism and treatment efficiency were cold, warm, neutral, pungent, sweet, bitter, lung meridian, spleen meridian, liver meridian, kidney meridian and clearing heat. Among them, Siraitia grosvenorii, Poria with hostwood, Perilla frutescens, and Radix Platycodi were all medicine and food homologous Chinese herbal medicines. Conclusions: The increase of CXCL10 and CXCL5 expression levels can increase the risk of VD, and the increase of IL-13 and IL-20 RA expression levels can reduce the risk of VD. Siraitia grosvenorii and other Chinese herbal medicines might be potential sources of therapeutic drugs for the treatment of VD. Medicine and food homologous Chinese herbal medicines, such as Siraitia grosvenorii, Poria with hostwood, Perilla frutescens, and Radix Platycodi, may help the elderly population with corresponding Traditional Chinese Medicine (TCM) constitutions to prevent VD.

Analysis of causal relationship between blood metabolites and prostate cancer by two-sample Mendelian randomization

Objective:To investigate the causal relationship between blood metabolite levels and the occurrence of prostate cancer by using two-sample Mendelian randomization method.Methods:Pooled data from public databases for genome-wide association analyses of blood metabolites and prostate cancer were selected,and inverse variance weighting(IVW)was used as the primary method for estimating the causal effects,while heterogeneity tests,gene multiplicity tests and sensitivity analyses were performed to assess the stability and reliability of the results.Results:A total of six known metabolites were found to potentially increase the risk of prostate cancer development(P<0.05),namely fructose,allantoin,5-hydroxytryptophan,potassium ketoisocaproate,glycyltryptophan,and 1-heptadecanoyl-glycerol-3-phosphorylcholine,with no heterogeneity or genetic pleiotropy found.Conclusion:Six known blood metabolites may be potential risk factors for prostate cancer development in European populations.

What-If XAI Framework (WiXAI): From Counterfactuals towards Causal Understanding

People learn causal relations since childhood using counterfactual reasoning. Counterfactual reasoning uses counterfactual examples which take the form of “what if this has happened differently”. Counterfactual examples are also the basis of counterfactual explanation in explainable artificial intelligence (XAI). However, a framework that relies solely on optimization algorithms to find and present counterfactual samples cannot help users gain a deeper understanding of the system. Without a way to verify their understanding, the users can even be misled by such explanations. Such limitations can be overcome through an interactive and iterative framework that allows the users to explore their desired “what-if” scenarios. The purpose of our research is to develop such a framework. In this paper, we present our “what-if” XAI framework (WiXAI), which visualizes the artificial intelligence (AI) classification model from the perspective of the user’s sample and guides their “what-if” exploration. We also formulated how to use the WiXAI framework to generate counterfactuals and understand the feature-feature and feature-output relations in-depth for a local sample. These relations help move the users toward causal understanding.

Causal Inference

Causal inference is a powerful modeling tool for explanatory analysis,which might enable current machine learning to become explainable.How to marry causal inference with machine learning to develop explainable artificial intelligence(XAI)algorithms is one of key steps toward to the artificial intelligence 2.0.With the aim of bringing knowledge of causal inference to scholars of machine learning and artificial intelligence,we invited researchers working on causal inference to write this survey from different aspects of causal inference.This survey includes the following sections:“Estimating average treatment effect:A brief review and beyond”from Dr.Kun Kuang,“Attribution problems in counterfactual inference”from Prof.Lian Li,“The Yule–Simpson paradox and the surrogate paradox”from Prof.Zhi Geng,“Causal potential theory”from Prof.Lei Xu,“Discovering causal information from observational data”from Prof.Kun Zhang,“Formal argumentation in causal reasoning and explanation”from Profs.Beishui Liao and Huaxin Huang,“Causal inference with complex experiments”from Prof.Peng Ding,“Instrumental variables and negative controls for observational studies”from Prof.Wang Miao,and“Causal inference with interference”from Dr.Zhichao Jiang.

Causal Stability Conditions for General Relativistic Spacetimes

A brief overview of some open questions in general relativity with important consequences for causality theory is presented, aiming to a better understanding of the causal structure of the spacetime. Special attention is accorded to the problem of fundamental causal stability conditions. Several questions are raised and some of the potential consequences of recent results regarding the causality problem in general relativity are presented. A key question is whether causality violating regions are locally allowed. The new concept of almost stable causality is introduced; meanwhile, related conditions and criteria for the stability and almost stability of the causal structure are discussed.

CAUSALITY DIAGRAM BASED SAFETY ANALYSIS OF MICRO TURBOJET ENGINE

An improved safety analysis based on the causality diagram for the complex system of micro aero-engines is presented.The study is examined by using the causality diagram in analytical failure cases due to rupture or pentration in the receiver of micro turbojet engine casing,and the comparisons are also made with the results from the traditional fault tree analysis.Experimental results show two main advantages：（1）Quantitative analysis which is more reliable for the failure analysis in jet engines can be produced by the causality diagram analysis;（2）Graphical representation of causality diagram is easier to apply in real test cases and more effective for the safety assessment.

A Kind of Fuzzy Causal Diagnosis Method

Aim To improve the causal diagnosis method presented by Bandekar and propose a new method of finding the root fault order according to the fault possibility by means of numerical calculation. Methods Based on the causal graph, by utilization of fuzzified threshold value and fuzzy discrimination matrix, a kind of fuzzy causal diagnosis method was given and the fault possibility of each elements in the root fault candidate set (RFCS) was obtained. Results and Conclusion The order of each element in the RFCS can be obtained by the fault possibility, which makes the location of fault much easier. The diagnosis speed of this method is quite high, and by means of the fuzzified threshold value and fuzzy discrimination matrix, the result is more robust to noises and bad parameter's choice.

含causal算子分数阶非线性微分方程的拟线性方法

采用拟线性化方法讨论了含causal算子的分数阶非线性微分方程初值问题,通过构造2个单调迭代序列,证明了它们一致且平方收敛于给出问题的解.

Causality Diagram-based Scheduling Approach for Blast Furnace Gas System

Rational use of blast furnace gas(BFG) in steel industry can raise economic profit, save fossil energy resources and alleviate the environment pollution. In this paper, a causality diagram is established to describe the causal relationships among the decision objective and the variables of the scheduling process for the industrial system, based on which the total scheduling amount of the BFG system can be computed by using a causal fuzzy C-means(CFCM) clustering algorithm. In this algorithm,not only the distances among the historical samples but also the effects of different solutions on the gas tank level are considered.The scheduling solution can be determined based on the proposed causal probability of the causality diagram calculated by the total amount and the conditions of the adjustable units. The causal probability quantifies the impact of different allocation schemes of the total scheduling amount on the BFG system. An evaluation method is then proposed to evaluate the effectiveness of the scheduling solutions. The experiments by using the practical data coming from a steel plant in China indicate that the proposed approach can effectively improve the scheduling accuracy and reduce the gas diffusion.