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Results for “causality”

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PubMed2005

Causal protein-signaling networks derived from multiparameter single-cell data.

Machine learning was applied for the automated derivation of causal influences in cellular signaling networks. This derivation relied on the simultaneous measurement of multiple phosphorylated protein and phospholipid components in thousands of individual primary human immune system cells. Perturbing these cells with molecular interventions drove the ordering of connections between pathway components, wherein Bayesian network computational methods automatically elucidated most of the traditionally reported signaling relationships and predicted novel interpathway network causalities, which we verified experimentally. Reconstruction of network models from physiologically relevant primary single cells might be applied to understanding native-state tissue signaling biology, complex drug actions, and dysfunctional signaling in diseased cells.

Algorithms↗

PubMed2026

Emerging tick-borne viral diseases in East Asia: pathology-driven insights into pathogenesis and disease causality.

SUMMARYTick-borne viral infections have emerged as a significant and growing public health concern. In East Asia, severe fever with thrombocytopenia syndrome (SFTS) has served as a prototypical disease in which pathological analyses have substantially advanced the understanding of disease pathogenesis. SFTS is characterized by profound immune dysregulation driven by viral tropism for plasmablast-lineage B cells, leading to cytokine storm and hemophagocytic syndrome. Complementary analyses of human clinical specimens and experimental animal models, including cats and ferrets, have provided critical insights into the immunopathogenesis of SFTS. The recent identification of additional tick-borne viruses, including Oz virus (OZV), Yezo virus (YEZV), and Alongshan virus (ALSV), has further expanded the spectrum of emerging infections in this region. Notably, pathological investigation of a fatal human case of OZV infection demonstrated direct viral localization within cardiomyocytes, establishing a causal link between infection and fulminant myocarditis and highlighting a distinct organ-specific pathogenic mechanism. Despite the advances in genomic technologies that enable rapid detection of novel viruses, establishing causal relationships between viral presence and disease remains a major challenge. Tissue-based pathological approaches, particularly in situ localization of viral components, are, therefore, essential for defining disease mechanisms and confirming etiological roles. This review provides a comprehensive synthesis of tick-borne viral infections in East Asia, with particular emphasis on Japan, integrating pathological, virological, and clinical perspectives. It also identifies key knowledge gaps and underscores the importance of a synergistic One Health framework that incorporates both human and veterinary pathology to advance the understanding and control of these emerging diseases.

One Health↗

PubMed1994

Significant increase in trisomy 21 in Berlin nine months after the Chernobyl reactor accident: temporal correlation or causal relation?

OBJECTIVE: To assess whether the increased prevalence of trisomy 21 in West Berlin in January 1987 might have been causally related to exposure to ionising radiation as a result of the Chernobyl reactor accident or was merely a chance event. DESIGN: Analysis of monthly prevalence of trisomy 21 in West Berlin from January 1980 to December 1989. SETTING: Confines of West Berlin. RESULTS: Owing to the former "island" situation of West Berlin and its well organised health services, ascertainment of trisomy 21 was thought to be almost complete. A cluster of 12 cases occurred in January 1987 as compared with two or three expected. After exclusion of factors that might have explained the increase, including maternal age distribution, only exposure to radiation as a result of the Chernobyl reactor accident remained. In six of seven cases that could be studied cytogenetically the extra chromosome was of maternal origin, confirming that nondisjunction had occurred at about the time of conception. CONCLUSION: On the basis of two assumptions--(a) that maternal meiosis is an error prone process susceptible to exogenous factors at the time of conception; (b) that owing to the high prevalence of iodine deficiency in Berlin a large amount of iodine-131 would have been accumulated over a short period--it is concluded that the increased prevalence of trisomy 21 in West Berlin in January 1987 was causally related to a short period of exposure to ionising radiation as a result of the Chernobyl reactor accident.

Accidents↗

PubMed2002

Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.

OBJECTIVE: To assess whether the association of serum homocysteine concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal and, if so, to quantify the effect of homocysteine reduction in preventing them. DESIGN: Meta-analyses of the above three diseases using (a) 72 studies in which the prevalence of a mutation in the MTHFR gene (which increases homocysteine) was determined in cases (n=16 849) and controls, and (b) 20 prospective studies (3820 participants) of serum homocysteine and disease risk. MAIN OUTCOME MEASURES: Odds ratios of the three diseases for a 5 micromol/l increase in serum homocysteine concentration. RESULTS: There were significant associations between homocysteine and the three diseases. The odds ratios for a 5 micromol/l increase in serum homocysteine were, for ischaemic heart disease, 1.42 (95% confidence interval 1.11 to 1.84) in the genetic studies and 1.32 (1.19 to 1.45) in the prospective studies; for deep vein thrombosis with or without pulmonary embolism, 1.60 (1.15 to 2.22) in the genetic studies (there were no prospective studies); and, for stroke, 1.65 (0.66 to 4.13) in the genetic studies and 1.59 (1.29 to 1.96) in the prospective studies. CONCLUSIONS: The genetic studies and the prospective studies do not share the same potential sources of error, but both yield similar highly significant results-strong evidence that the association between homocysteine and cardiovascular disease is causal. On this basis, lowering homocysteine concentrations by 3 micromol/l from current levels (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16% (11% to 20%), deep vein thrombosis by 25% (8% to 38%), and stroke by 24% (15% to 33%).

Cohort Studies↗

PubMed2003

Group B streptococcus carriage and vulvovaginal symptoms: causal or casual? A case-control study in a GUM clinic population.

OBJECTIVES: The isolation of group B streptococcus (GBS) on routine swabs taken from genitourinary medicine (GUM) clinic attendees is a common finding. The relation of GBS to vulvovaginal symptoms is unclear, creating confusion about management. This case-control study tested the hypothesis that detection of GBS on routine clinical specimens is not causally related to vulvovaginal symptoms in female GUM clinic attendees. METHODS: Data were collected on all female GUM clinic attendees who had GBS isolated from anogenital swabs between July 1999 and July 2001. Controls were randomly selected from all new and rebooking female GUM clinic attendees. Controls were group matched for age with cases and were included only if a sexual health screen was performed and the results of this were available. RESULTS: 118 cases and 308 controls were identified during the study period. There was no significant difference between cases and controls in patient demographic or behavioural characteristics, the presence of genital co-infection, or vulvovaginal symptoms. There was no relation between symptoms and quantitative growth of GBS reported by the laboratory in either cervical or urethral swabs. Only nine cases had high vaginal swabs taken, in whom there was a significant association between a heavy growth of GBS and vulvovaginal symptoms (p=0.008). CONCLUSION: The isolation of GBS from routinely collected genital swabs in female attendees of a GUM clinic is not causally related to vulvovaginal symptoms. We recommend that patients should receive this advice and should not be treated with antibiotic therapy for this indication.

Adult↗

PubMed2000

Assessing baroreflex gain from spontaneous variability in conscious dogs: role of causality and respiration.

A double exogenous autoregressive (XXAR) causal parametric model was used to estimate the baroreflex gain (alpha(XXAR)) from spontaneous R-R interval and systolic arterial pressure (SAP) variabilities in conscious dogs. This model takes into account 1) effects of current and past SAP variations on the R-R interval (i.e., baroreflex-mediated influences), 2) specific perturbations affecting R-R interval independently of baroreflex circuit (e.g., rhythmic neural inputs modulating R-R interval independently of SAP at frequencies slower than respiration), and 3) influences of respiration-related sources acting independently of baroreflex pathway (e.g., rhythmic neural inputs modulating R-R interval independently of SAP at respiratory rate, including the effect of stimulation of low-pressure receptors). Under control conditions, alpha(XXAR) = 14.7 +/- 7.2 ms/mmHg. It decreases after nitroglycerine infusion and coronary artery occlusion, even though the decrease is significant only after nitroglycerine, and it is completely abolished by total arterial baroreceptor denervation. Moreover, alpha(XXAR) is comparable to or significantly smaller than (depending on the experimental condition) the baroreflex gains derived from sequence, power spectrum [at low frequency (LF) and high frequency (HF)], and cross-spectrum (at LF and HF) analyses and from less complex causal parametric models, thus demonstrating that simpler estimates may be biased by the contemporaneous presence of regulatory mechanisms other than baroreflex mechanisms.

Animals↗

PubMed2006

Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells.

L-Asparaginase (l-ASP), a bacterial enzyme used since the 1970s to treat acute lymphoblastic leukemia, selectively starves cells that cannot synthesize sufficient asparagine for their own needs. Molecular profiling of the NCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase (ASNS) expression and DNA copy number with sensitivity to l-ASP in the leukemia and ovarian cancer cell subsets. To assess whether the ovarian relationship is causal, we used RNA interference to silence ASNS in three ovarian lines and observed 4- to 5-fold potentiation of sensitivity to l-ASP with two of the lines. For OVCAR-8, the line that expresses the least ASNS, the potentiation was >500-fold. Significantly, that potentiation was >700-fold in the multidrug-resistant derivative OVCAR-8/ADR, showing that the causal relationship between ASNS expression and l-ASP activity survives development of classical multidrug resistance. Tissue microarrays confirmed low ASNS expression in a subset of clinical ovarian cancers as well as other tumor types. Overall, this pharmacogenomic/pharmacoproteomic study suggests the use of l-ASP for treatment of a subset of ovarian cancers (and perhaps other tumor types), with ASNS as a biomarker for patient selection.

Antineoplastic Agents↗

PubMed1987

Assessing the effects of psychotherapy. V. Nonexperimental methods in the analysis of causality.

On the basis of an explication of the experimental method of control for causal order and spuriousness, nonexperimental alternatives are explored. Controlling for both causal order and spuriousness, the partial correlation approach is explained, particularly as developed in structural equation models. Advantages and disadvantages in comparison with the experimental method are discussed.

Humans↗

PubMed2005

Effects of caregivers' perceived stigma and causal beliefs on patients' adherence to antidepressant treatment.

OBJECTIVE: Nonadherence to prescribed medications is a significant problem in the treatment of mood disorders. Previously proposed adherence models have not been sufficiently accurate in identifying patients who do not adhere to treatment. This study evaluated the importance of the social context in adherence by using a prospective, longitudinal analysis. Specifically, this study evaluated the effects of caregivers' causal beliefs about depression and their perceptions of stigma on three-month treatment adherence among patients with depression. METHODS: Fifty patients with major depressive disorder and their primary caregivers were identified at a psychiatric hospital's outpatient clinic. Attributions for the causes of depression (either cognitive and attitudinal or medical and biological) and perceived stigma were assessed among caregivers at baseline, and patients' adherence was evaluated three-months after treatment began. RESULTS: Data were available for 47 patients at follow-up. Caregivers' attribution of depression to cognitive and attitudinal problems significantly predicted patients' decreased adherence. However, the degree of patients' adherence was not predicted by caregivers' attributions to medical and biological causes and caregivers' perceived stigma. CONCLUSIONS: The findings stress the importance of patients' social environment in determining treatment adherence and the necessity of educating caregivers about the impact that their causal attributions have on patients' behavior. Involving caregivers in treatment may improve their attitude toward patients with depression and, in doing so, enhance patients' adherence and outcome.

Adult↗

PubMed2002

Causal factors of corporate crime in Taiwan: qualitative and quantitative findings.

Street crimes are a primary concern of most criminologists in Taiwan. In recent years, however, crimes committed by corporations have increased greatly in this country. Employing the empirical approach to collect data about causal factors of corporate crime, the research presented in this article is the first systematic empirical study concerning corporate crime in Taiwan. The research sample was selected from a corporation with a criminal record of pollution caused by the release of toxic chemicals into the environment and a corporation with no criminal record. Questionnaire survey and interviews of corporate employees and managers were conducted, and secondary data were collected from official agencies. This research indicated the causal factors of corporate crime as follows: the failure of government regulation, lack of corporate self-regulation, lack of public concern about corporate crime, corporate mechanistic structure, and the low self-control tendency of corporate managers.

Crime↗

PubMedDate not supplied

Does identification of the causal organism of corneal ulcers influence the outcome?

PURPOSE: To investigate whether identification of the causal organism in corneal ulcers influences their outcome. METHODS: We retrospectively studied 114 patients, 72 males and 42 females aged 6-89 years, admitted to this eye clinic during the years 1994-2000 on account of an infectious corneal ulcer. Their examination included a detailed history, visual acuity measurement, and biomicroscopy in everyday follow-up. The ulcers were classified according to their severity and outcome. We assessed the cases where cultures had been done, reviewed the results, and searched for a possible correlation between the outcome and the fact of culturing the ulcer and identifying the causal organism. RESULTS: Of the 114 corneal ulcers studied, 23 were mild, 49 moderate, and 42 severe. Fifty (44%) had not been cultured, but 64 ulcers (56%) had been cultured, with a positive result in 37 cases (58%), Staphylococcus and Pseudomonas species being the most common organisms found. In moderate and severe ulcers, there was a tendency to a higher proportion of successful outcome for cultured ulcers, but with no significant correlation. CONCLUSIONS: Despite a tendency towards favorable results in culture-positive corneal ulcers, the influence of the detection of the organism on their outcome has not been proved. The role of the initial broad-spectrum antibiotic therapy remains important.

Adolescent↗

PubMed2001

Theory of mind, causal attribution and paranoia in Asperger syndrome.

Theory of mind (ToM) deficits are central to autistic spectrum disorders, including Asperger syndrome. Research in psychotic disorders has developed a cognitive model of paranoid delusions involving abnormal causal attributions for negative events. Possible aetiologies of these include deficits in social reasoning, specifically ToM. The present study investigated this attributional model of paranoia in Asperger syndrome. Participants diagnosed with Asperger syndrome scored significantly higher on a measure of paranoia and lower on a measure of ToM, compared with the control group. They did not differ in self-concept and causal attributions, contrary to the attributional model of paranoia. A regression analysis highlighted private self-consciousness as the only predictor of paranoia. The theoretical and clinical implications of these findings are discussed.

Adolescent↗

PubMed2006

Causal inference of regulator-target pairs by gene mapping of expression phenotypes.

BACKGROUND: Correlations between polymorphic markers and observed phenotypes provide the basis for mapping traits in quantitative genetics. When the phenotype is gene expression, then loci involved in regulatory control can theoretically be implicated. Recent efforts to construct gene regulatory networks from genotype and gene expression data have shown that biologically relevant networks can be achieved from an integrative approach. In this paper, we consider the problem of identifying individual pairs of genes in a direct or indirect, causal, trans-acting relationship. RESULTS: Inspired by epistatic models of multi-locus quantitative trait (QTL) mapping, we propose a unified model of expression and genotype to identify quantitative trait genes (QTG) by extending the conventional linear model to include both genotype and expression of regulator genes and their interactions. The model provides mapping of specific genes in contrast to standard linkage approaches that implicate large QTL intervals typically containing tens of genes. In simulations, we found that the method can often detect weak trans-acting regulators amid the background noise of thousands of traits and is robust to transcription models containing multiple regulator genes. We reanalyze several pleiotropic loci derived from a large set of yeast matings and identify a likely alternative regulator not previously published. However, we also found that many regulators can not be so easily mapped due to the presence of cis-acting QTLs on the regulators, which induce close linkage among small neighborhoods of genes. QTG mapped regulator-target pairs linked to ARN1 were combined to form a regulatory module, which we observed to be highly enriched in iron homeostasis related genes and contained several causally directed links that had not been identified in other automatic reconstructions of that regulatory module. Finally, we also confirm the surprising, previously published results that regulators controlling gene expression are not enriched for transcription factors, but we do show that our more precise mapping model reveals functional enrichment for several other biological processes related to the regulation of the cell. CONCLUSION: By incorporating interacting expression and genotype, our QTG mapping method can identify specific regulator genes in contrast to standard QTL interval mapping. We have shown that the method can recover biologically significant regulator-target pairs and the approach leads to a general framework for inducing a regulatory module network topology of directed and undirected edges that can be used to identify leads in pathway analysis.

Algorithms↗

PubMed2004

Years of Life Lost due to exposure: Causal concepts and empirical shortcomings.

Excess Years of Life Lost due to exposure is an important measure of health impact complementary to rate or risk statistics. I show that the total excess Years of Life Lost due to exposure can be estimated unbiasedly by calculating the corresponding excess Years of Potential Life Lost given conditions that describe study validity (like exchangeability of exposed and unexposed) and assuming that exposure is never preventive. I further demonstrate that the excess Years of Life Lost conditional on age at death cannot be estimated unbiasedly by a calculation of conditional excess Years of Potential Life Lost without adopting speculative causal models that cannot be tested empirically. Furthermore, I point out by example that the excess Years of Life Lost for a specific cause of death, like lung cancer, cannot be identified from epidemiologic data without assuming non-testable assumptions about the causal mechanism as to how exposure produces death. Hence, excess Years of Life Lost estimated from life tables or regression models, as presented by some authors for lung cancer or after stratification for age, are potentially biased. These points were already made by Robins and Greenland 1991 reasoning on an abstract level. In addition, I demonstrate by adequate life table examples designed to critically discuss the Years of Potential Life Lost analysis published by Park et al. 2002 that the potential biases involved may be fairly extreme. Although statistics conveying information about the advancement of disease onset are helpful in exposure impact analysis and especially worthwhile in exposure impact communication, I believe that attention should be drawn to the difficulties involved and that epidemiologists should always be aware of these conceptual limits of the Years of Potential Life Lost method when applying it as a regular tool in cohort analysis.

Journal Article↗

PubMed2006

Causal analysis of case-control data.

In a series of papers, Robins and colleagues describe inverse probability of treatment weighted (IPTW) estimation in marginal structural models (MSMs), a method of causal analysis of longitudinal data based on counterfactual principles. This family of statistical techniques is similar in concept to weighting of survey data, except that the weights are estimated using study data rather than defined so as to reflect sampling design and post-stratification to an external population. Several decades ago Miettinen described an elementary method of causal analysis of case-control data based on indirect standardization. In this paper we extend the Miettinen approach using ideas closely related to IPTW estimation in MSMs. The technique is illustrated using data from a case-control study of oral contraceptives and myocardial infarction.

Journal Article↗

PubMed2006

Causal criteria and counterfactuals; nothing more (or less) than scientific common sense.

Two persistent myths in epidemiology are that we can use a list of "causal criteria" to provide an algorithmic approach to inferring causation and that a modern "counterfactual model" can assist in the same endeavor. We argue that these are neither criteria nor a model, but that lists of causal considerations and formalizations of the counterfactual definition of causation are nevertheless useful tools for promoting scientific thinking. They set us on the path to the common sense of scientific inquiry, including testing hypotheses (really putting them to a test, not just calculating simplistic statistics), responding to the Duhem-Quine problem, and avoiding many common errors. Austin Bradford Hill's famous considerations are thus both over-interpreted by those who would use them as criteria and under-appreciated by those who dismiss them as flawed. Similarly, formalizations of counterfactuals are under-appreciated as lessons in basic scientific thinking. The need for lessons in scientific common sense is great in epidemiology, which is taught largely as an engineering discipline and practiced largely as technical tasks, making attention to core principles of scientific inquiry woefully rare.

Journal Article↗

PubMed2026

Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours.

BACKGROUND: Alcohol use disorder (AUD) represents a tremendous societal burden, yet few efficacious therapies are available and widely used. Pre-clinical and human observational data support fibroblast growth factor 21 (FGF21) as a promising therapeutic target for the treatment of AUD. The objective of this study is to identify a robust genetic instrument for FGF21 agonism and leverage it to explore the effects of FGF21 agonism on AUD and related traits, as well as metabolic outcomes more widely. METHODS: We first compared associations with the positive control outcomes of liver fat and liver cirrhosis risk for the FGF21 cis-protein quantitative trait locus (cis-pQTL) (rs838131) to those for the common allele FGF21 L174P missense variant (rs739320). Having identified the L174P missense variant as a plausible genetic instrument, we subsequently performed association analyses investigating effects on AUD, related traits, and metabolic outcomes more widely. Finally, we performed colocalisation analyses to test whether observed association results reflect a causal mechanism that overlaps with the clinical effects of FGF21 on liver fat and liver cirrhosis. RESULTS: Consistent association and colocalisation evidence support a protective association between genetically predicted FGF21 agonism and alcohol consumption (association p = 1 × 10-18, colocalisation posterior probability = 0.90), problematic alcohol use (association p = 0.02, posterior probability = 0.64), and AUD (association p = 9 × 10-8, posterior probability = 0.97). Similar evidence was also observed for favourable effects of FGF21 on improving kidney function, lowering triglyceride levels, lowering proportional energy intake from carbohydrates, increasing proportional energy intake from protein and fat, increasing body weight and lowering waist-to-hip ratio. CONCLUSIONS: This study identifies a genetic instrument for FGF21 effects to provide causal human evidence supporting favourable effects of FGF21 analogues for the treatment of AUD and related traits, as well as on metabolic outcomes more broadly. Further clinical study is duly warranted.

Humans↗

PubMed2024

Causal effect of the age at first birth with depression: a mendelian randomization study.

BACKGROUND: This study aimed to explore the causal relationship between age at first birth (AFB) and depression. METHODS: Using the univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) methods to examine the potential correlation between age at first birth (AFB) and major depressive disorder and postpartum depression. A public database was used to obtain the genome-wide association studies (GWAS) summary data. We put inverse-variance-weighted (IVW) as the primary method in Mendelian randomization (MR) analysis and used sensitivity analysis to confirm the robustness of our result. RESULTS: We found a significant causal association between AFB and major depressive disorder by using the IVW algorithm (odd ratio [OR] 0.826; 95% confidence interval [CI] 0.793 - 0.861; P = 4.51 × 10- 20). MR-Egger, weighted median, simple mode and weighted mode method concluded the same result (P < 0.05). During the sensitivity analysis, the heterogeneity test (Q-value = 55.061, df = 48, P = 2.81 × 10- 01, I2 = 12.82%) and the leave-one-out plot analysis confirmed the stability of the results. The outcomes of the pleiotropy test (MR-Egger intercept = 8.932 × 10- 3. SE = 6.909 × 10- 3. P = 2.02 × 10- 01) and MR_PRESSO global test (P = 2.03 × 10- 01) indicated there is no pleiotropy. CONCLUSION: There is solid evidence that a higher age at first birth is associated with a lower risk of major depressive disorder.

Humans↗