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PubMed2025

Causal effect of three autoimmune diseases on brain functional networks and cerebrospinal fluid metabolites to underlie the pathogenesis of autoimmune psychosis: a two-sample mendelian randomization analysis.

BACKGROUND: Autoimmune diseases such as Systemic Lupus Erythematosus (SLE), Sjögren's Syndrome (SS), and Hashimoto's Thyroiditis (HT) frequently exhibit neuropsychiatric manifestations, including cognitive impairment, depression, anxiety, and so on, yet the exact pathogenesis underlying this association remain incompletely understood. Dysfunction of brain resting-state functional networks and cerebrospinal fluid (CSF) metabolite disturbances have been widely reported in psychiatric disorders. However, the application of resting-state functional magnetic resonance imaging (rsfMRI) and CSF metabolomics in the diagnosis and monitoring of autoimmune psychosis is still limited. METHODS: A two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationships between three autoimmune diseases (SLE, SS, and HT, n = 14,267 to 402,090 individuals) and 191 rsfMRI phenotypes (n = 47,276 individuals), as well as 338 CSF metabolites. The genome-wide association study (GWAS) of three autoimmune diseases was used as the exposure, whereas rsfMRI phenotypes and 338 CSF metabolites were treated as the outcome. Inverse variance weighted (IVW) with P value < 0.05 was regarded as the primary approach for calculating causal estimates. Additionally, the false discovery rate (FDR)-adjusted P value (PFDR) < 0.05 was utilized to account for multiple testing. MR Egger method, weighted median method, simple mode method and weighted mode method were used for sensitive analysis. RESULTS: Our analyses identified 5 causal relationships between SLE and the 191 rsfMRI phenotypes, 48 between SS and the 191 rsfMRI phenotypes, and 4 between HT and the 191 rsfMRI phenotypes. Additionally, we found 8 causal relationships between HT and CSF metabolites. Furthermore, all three diseases were significantly associated with the temporal lobe and triple networks (default mode network (DMN), salience network (SN), and central executive network (CEN)), which are the core brain regions and functional networks for cognition. Following FDR correction, 6 causal relationships between SS and the 191 rsfMRI phenotypes were further validated. CONCLUSIONS: Our study pinpoints important brain functional networks and CSF metabolites potentially implicated in the pathogenesis of psychiatric disorders associated with autoimmune diseases and highlights critical brain regions for the development of novel therapeutics.

Humans↗

PubMed2001

[Causal inference in medicine--decision making].

In the field of occupational medicine, either when we consider some preventive plans or when we make decisions to compensate for occupational diseases, it has been necessary to discuss causality between work and disease. Furthermore, epidemiologic causality has recently been used in risk assessment in occupational and environmental settings. We have shown that the law of causality in medicine is recognized as probability and continuous variables. Such a law of causality has been recognized in the same way as probability in physics, too, and has been regarded as a model of science. Physicists and mathematicians had claimed the importance of probability in causal inference as well as the principle of uncertainty before it was discovered. We, then, explained Etiologic Fraction (EF), Attributable Proportion for the Exposed Population (APE), Probability of Causation (PC), and so on. The PC has been used to ascertain the conditional probability in an individual case of a disease having been caused by a particular prior exposure, by using the experience of exposed populations to determine the appropriate relative risk, and this has been used for compensation for exposed cases. Next the applicability of information from a population to individuals was presented. Third, we provided a brief historical aspect of epidemiology. The evolutions in Epidemiology have been very rapid, so we pointed out that, in Japan, we could observe many incommensurable phenomena in epidemiologists and physicians depending on the era which was studied by them. Fourth, we discussed judgement and political application based on epidemiologic evidence, using Yanagimoto's classification is also taken or not should be estimated and compared. We presented several examples of reasoning in judgements. Lastly, we discussed several tasks and assignments for the future of epidemiology.

Causality↗

PubMed2000

Causal attributions in Brazilian children's reasoning about health and illness.

INTRODUCTION: At a time when a great number of diseases can be prevented by changing one's habits and life style, investigations have focused on understanding what adults and children believe to be desirable health practices and uncovering the factors associated with successful adherence to such practices. For these, causal attributions for health and illness were investigated among 96 Brazilian elementary school students. METHODS: Ninety six subjects, aged 6 to 14, were interviewed individually and their causal attributions were assessed through 14 true-false items (e.g. people stay well [healthy] because they are lucky). The relationship between the children's causal attributions and demographic characteristics were also examined. RESULTS: Overall, the results were consistent with previous researches. "Taking care of oneself" was considered the most important cause of good health. "Viruses and germs" and "lack of self-care" were the most selected causes of illness. Analyses revealed significant relationship between subjects' causal attribution and their age, school grade level, socioeconomic status and gender. CONCLUSIONS: The study findings suggest that there may be more cross-cultural similarities than differences in children's causal attributions for health and illness. Finding ways to help individuals engage in appropriate preventive-maintenance health practices without developing an exaggerated notion that the individuals can control their own health and illness is a challenge which remains to be addressed by further research.

Adolescent↗

PubMed1989

[A study of relation between hopelessness and causal attribution in school-aged children].

This study was conducted to investigate the relation between hopelessness and causal attribution in Japanese school-aged children. In Study 1, the Japanese edition of hopelessness scale for children developed by Kazdin, French, Unis, Esveldt-Dawsan, and Sherick (1983) was constructed. Seventeen original items were translated into Japanese and they were administrated to 405 fifth- and sixth-graders. All of the items could be included to the Japanese edition of hopelessness scale. The reliability and validity was examined. In Study 2, the relation between hopelessness and causal attribution in children were investigated. The causal attribution questionnaire developed by Higuchi, Kambare, and Otsuka (1983) and the hopelessness scale developed by Study 1 were administered to 188 sixth-graders. Children with high scores in hopelessness scale significantly attributed negative events to much more effort factor than children with low scores. It supports neither the reformulated learned helplessness model nor the causal attribution theory of achievement motivation. It was explained mainly from points of self-serving attribution, cultural difference, and social desirability. Some questions were discussed for developing studies on depression and causal attribution in Japan.

Achievement↗

PubMedDate not supplied

[Causality in nephrology: study design and objectives of future research].

BACKGROUND: Causality has to be assessed by randomised controlled trials. However, since these are not always ethically or technically possible, other study designs such as cohort studies, case-control and cross-sectional analytic studies may be used. METHODS: In this review, we focus on the strengths and limitations of epidemiological studies whose aim is to identify the causal relationship between study factor and outcome (cohort studies, case-control studies, cross-sectional analytic studies). We also introduce the absolute and non-absolute parameters useful in determining the causal relationship in epidemiological studies. RESULTS: To establish a causal relationship between a factor and an outcome, exposure must precede the outcome, the association must not be due to chance, bias, confounding or misclassification. It is important when reading this kind of research papers that all these factors are properly considered. Studies in which strong associations are documented, whereby a dose-effect relationship exists, and those which are consistent with the results of previous epidemiological studies and document biologically plausible associations are generally stronger evidence than those in which these criteria are not found. CONCLUSIONS: The design and conduct of valid cohort, case-control and other type of studies, when randomised trials are unfeasible or unethical to answer causality and intervention questions, is a challenge for the nephrology community, presently lacking valid clinical evidence and adequate answers to many questions.

Biomedical Research↗

PubMed2005

Epidemiological causality.

Epidemiological methods, which combine population thinking and group comparisons, can primarily identify causes of disease in populations. There is therefore a tension between our intuitive notion of a cause, which we want to be deterministic and invariant at the individual level, and the epidemiological notion of causes, which are invariant only at the population level. Epidemiologists have given heretofore a pragmatic solution to this tension. Causal inference in epidemiology consists in checking the logical coherence of a causality statement and determining whether what has been found grossly contradicts what we think we already know: how strong is the association? Is there a dose-response relationship? Does the cause precede the effect? Is the effect biologically plausible? Etc. This approach to causal inference can be traced back to the English philosophers David Hume and John Stuart Mill. On the other hand, the mode of establishing causality, devised by Jakob Henle and Robert Koch, which has been fruitful in bacteriology, requires that in every instance the effect invariably follows the cause (e.g., inoculation of Koch bacillus and tuberculosis). This is incompatible with epidemiological causality which has to deal with probabilistic effects (e.g., smoking and lung cancer), and is therefore invariant only for the population.

Biology↗

PubMed1995

Does smoking cause low back pain? A review of the epidemiologic literature for causality.

BACKGROUND: Smoking has been associated with low back pain (LBP) in several epidemiologic studies but the results are contradictory. Despite this, smoking is often assumed to be a causative factor of LBP. STUDY OBJECTIVE: To appraise the epidemiologic literature to establish whether there is evidence for a causal link between smoking and LBP. DATA SOURCES: Twenty-two original research reports published between 1974 and 1993 were reviewed and a systematic investigation was made of eight of these, which were retained because they included study samples representative of their target populations. DATA SYNTHESIS: To uncover any evidence for a causal relationship between smoking and LBP, these eight reports were examined in detail for strength of association, dose-response effect, temporality and consistency of findings. RESULTS: Some studies found a positive association between smoking and LBP; when present, the strength of this association was generally small. Some associations remained unchanged after multivariate analysis, whereas others became statistically nonsignificant. Contradictory results were also noted in studies which reported on the dose-response relationship and time of exposure in relation to time of onset of LBP. There was inconsistency of findings within and between studies relating to LBP. However, the evidence was consistently against a causal association between smoking and sciatica/discal hernia. CONCLUSION: It cannot be clearly deduced whether smoking has a causal effect on LBP or whether the positive findings sometimes noted are linked to some other, still unidentified factor. However, there is clearly no proof supporting a causal association between smoking and sciatica/discal hernia.

Causality↗

PubMed1996

Children's and adults' memory for television stories: the role of causal factors, story-grammar categories, and hierarchical level.

What events from televised stories do preschool children and adults remember? In this study, we examined the extent to which 4-year-old and 6-year-old children's and adults' free recall of events from "Sesame Street" stories is determined by the role the events play in the story structure. Events varied with respect to 4 structural properties: number of causal connections, status on or off the story's causal chain, story-grammar category, and position in the story's hierarchical structure. There were systematic developmental differences in the effects of these properties on recall. First, memory at all ages was strongly influenced by the 2 causal factors, but effects of these factors increased with age. Second, children emphasized actions in their recall, whereas adults most frequently recalled protagonists' goals and events that initiated these goals. Third, children's recall increased as the hierarchical level of events increased, whereas adults most frequently recalled (causally more important) events at intermediate levels. These findings demonstrate that preschool children are already sensitive to structural features of televised narratives but that utilization of the causal-motivational structure of narratives increases systematically with age.

Adult↗

PubMed1998

Agents, vehicles, and causal inference in bacterial foodborne disease outbreaks: 82 reports (1986-1995).

OBJECTIVE: To examine the study design of, and the practice of causal inference in, investigations of bacterial foodborne disease outbreaks occurring in the United States and to summarize agents and vehicles identified. DESIGN: Retrospective study. PROCEDURE: An online medical reference database was searched for reports of bacterial foodborne disease outbreak investigations published between 1986 and 1995. Reports were retrieved and reviewed for use of 9 causal criteria in investigations. Information on etiologic agents, vehicles, seasonality, and primary study design from each outbreak was also retrieved. RESULTS: 82 reports were retrieved and reviewed. Coherence, consistency, temporality, and strength of association were the causal criteria most commonly used in foodborne disease outbreak investigations. Coherence was used in all investigations. The number of criteria used ranged from 3 to 7. Meat (n = 20) and eggs (12) were the most commonly implicated vehicles. Salmonella sp and Escherichia coli O157:H7 accounted for 55% of agents reportedly isolated. Cohort and case-control methods were the most common study designs. CLINICAL RELEVANCE: Patterns were found in the use of causal criteria in foodborne disease outbreak investigations. These criteria can provide veterinarians and other public health practitioners with a means to effectively conceptualize, communicate, and summarize causal conclusions. The 4 most commonly used criteria may represent core criteria that investigators consider most useful in explaining food-borne disease outbreaks.

Animals↗

PubMed1998

[Subjective causal scenarios for global environmental change].

Two studies are presented that investigate the assumptions that risk evaluation is based on subjective causal scenarios, and that the cognitive representation of global environmental risks is structured according to five causal levels: human attitudes, human activities, emissions or pollutions, environmental changes, and negative consequences. In study 1, 30 subjects listed in free-response format causes, consequences, and remedial measures for 14 environmental risks. Differences between predictive and diagnostic inferences were found: whereas subjects tend to assign immediate rather than mediated causes, they predominantly assign negative consequences for humans, irrespective of the length of the causal chain that leads to these consequences. In study 2, 41 subjects judged the overall similarity between 25 environmental risks. A multidimensional scaling analysis of these similarity judgments replicates the theoretically assumed five causal levels. Results of both studies support the assumptions that risk evaluation is based on implicit causal hypotheses and that the proposed five-level structure adequately describes the cognitive representation of environmental risks.

Adult↗

PubMed1982

Concepts in causality: chemically induced human urinary bladder cancer.

A significant portion of the incidence of human urinary bladder cancer can be attributed to occupational and cultural (tobacco smoking) situations associated with exposures to various arylamines, many of which represent established human carcinogens. A brief historical overview of research in bladder cancer causality indicates that the identification of causal agents and causal mechanism has been approached and rests upon information gathered at the organismal (geographical/historical), cellular, and molecular levels of biologic organization. This viewpoint speaks of a natural evolution within the biomedical sciences; a natural evolution from descriptive approaches to mechanistic approaches; and a natural evolution from more or less independent discipline-oriented approaches to hierarchically organized multidisciplinary approaches. Available information relevant to bladder cancer causality can be readily integrated into general conceptual frameworks to yield a hierarchial view of the natural history of urinary bladder cancer, a view consistent with contemporary natural systems and information theory and perhaps relevant also to other chemically induced epithelial cancers. Such frameworks are useful in appreciating the spatial and temporal boundaries and interrelationships in causality and the conceptual interrelationships within the biomedical sciences. Recent approaches in molecular epidemiology and the assessment of relative individual susceptibility to bladder cancer indicate that such frameworks are useful in forming hypotheses.

Animals↗

PubMed2004

Causal knowledge and imitation/emulation switching in chimpanzees (Pan troglodytes) and children (Homo sapiens).

This study explored whether the tendency of chimpanzees and children to use emulation or imitation to solve a tool-using task was a response to the availability of causal information. Young wild-born chimpanzees from an African sanctuary and 3- to 4-year-old children observed a human demonstrator use a tool to retrieve a reward from a puzzle-box. The demonstration involved both causally relevant and irrelevant actions, and the box was presented in each of two conditions: opaque and clear. In the opaque condition, causal information about the effect of the tool inside the box was not available, and hence it was impossible to differentiate between the relevant and irrelevant parts of the demonstration. However, in the clear condition causal information was available, and subjects could potentially determine which actions were necessary. When chimpanzees were presented with the opaque box, they reproduced both the relevant and irrelevant actions, thus imitating the overall structure of the task. When the box was presented in the clear condition they instead ignored the irrelevant actions in favour of a more efficient, emulative technique. These results suggest that emulation is the favoured strategy of chimpanzees when sufficient causal information is available. However, if such information is not available, chimpanzees are prone to employ a more comprehensive copy of an observed action. In contrast to the chimpanzees, children employed imitation to solve the task in both conditions, at the expense of efficiency. We suggest that the difference in performance of chimpanzees and children may be due to a greater susceptibility of children to cultural conventions, perhaps combined with a differential focus on the results, actions and goals of the demonstrator.

Animals↗

PubMed2026

Genetic Evidence That Stroke Causally Increases Circulating PDGFB Levels: a Two-Sample Mendelian Randomization Study.

Platelet-derived growth factor subunit B (PDGFB) is a key regulator of vascular remodeling, angiogenesis, and blood-brain barrier integrity. Although elevated PDGFB levels have been reported after ischemic injury, whether stroke liability itself causally influences circulating PDGFB levels remains unclear. We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effects of genetically predicted all stroke, ischemic stroke, and cardioembolic stroke on plasma PDGFB concentrations. Genetic instruments were obtained from large-scale GIGASTROKE genome-wide association studies, and outcome data were derived from a proteomics GWAS. Instruments were then filtered by removing variants associated with established cardiovascular risk factors in a phenome-wide screen and outliers identified by RadialMR. The inverse variance-weighted (IVW) method was used as the primary analysis, complemented by weighted median, weighted mode, and MR-Egger approaches. Sensitivity analyses included Cochran's Q statistics, MR-Egger intercept tests, single-SNP analyses, leave-one-out analyses, and MR-PRESSO. IVW analysis demonstrated a significant positive causal association between genetic liability to all stroke and plasma PDGFB levels (β = 0.209, SE = 0.062, 95% CI 0.088 to 0.331, p = 7.3 × 10-4). A similar association was observed for ischemic stroke (β = 0.155, SE = 0.059, 95% CI 0.039 to 0.270, p = 0.009), with directionally consistent results across sensitivity analyses. MR-Egger regression for ischemic stroke initially suggested pleiotropy.After removal of a radial-MR outlier (rs2289252), the intercept was attenuated and no longer statistically significant (- 0.0190, p = 0.282). In contrast, no evidence of a causal association was found between cardioembolic stroke liability and plasma PDGFB levels across all MR methods (β = - 0.078, SE = 0.087, 95% CI - 0.248 to 0.092, p = 0.368). These findings provide genetic evidence that liability to stroke, particularly ischemic stroke, is causally associated with increased circulating PDGFB levels, whereas cardioembolic stroke does not show such an effect. This suggests that elevated PDGFB reflects vascular responses specific to ischemic stroke rather than a general consequence of all stroke subtypes.

Humans↗

PubMed2002

Causal explanations of distress and general practitioners' assessments of common mental disorder among punjabi and English attendees.

BACKGROUND: The literature on the primary care assessment of mental distress among Indian subcontinent origin patients suggests frequent presentations to general practitioner, but rarely for recognisable psychiatric disorders. This study investigates whether cultural variations in patients' causal explanatory models account for cultural variations in the assessment of non-psychotic mental disorders in primary care. METHODS: In a two-phase survey, 272 Punjabi and 269 English subjects were screened. The second phase was completed by 209 and 180 subjects, respectively. Causal explanatory models were elicited as explanations of two vignette scenarios. One of these emphasised a somatic presentation and the other anxiety symptoms. Psychiatric disorder was assessed by GPs on a Likert scale and by a psychiatrist on the Clinical Interview Schedule. RESULTS: Punjabis more commonly expressed medical/somatic and religious beliefs. General practitioners were more likely to assess any subject giving psychological explanations to vignette A and English subjects giving religious explanations to vignette B as having a significant psychiatric disorder. Where medical/somatic explanations of distress were most prevalent in response to the somatic vignette, psychological, religious and work explanations were less prevalent among Punjabis but not among English subjects. Causal explanations did not fully explain cultural differences in assessments. CONCLUSIONS: General practitioners' assessments and causal explanations are related and influenced by culture, but causal explanations do not fully explain cultural differences in assessments.

Adolescent↗

PubMed1995

Cognition and causality, fiction and explanation.

The debate about the causal efficacy of cognition involves two overlapping but different issues: (1) whether explanatory fictions improve upon the power and utility of nonfictional explanations of behavior, and (2) whether any explanation, either purely empirical or purely inferential, can describe proximal causality in behavioral functioning. The resolution of the first issue depends on the purpose to which the explanation is to be put. The resolution of the second issue depends on the larger paradigmatic context in which causality is understood. In modern biosystemic models of behavior, linear causality is important only as a special case of the multidirectional and reciprocal causality which characterizes complex self-regulating systems.

Cognition↗

PubMed1985

The causal sequence on death certificates: errors affecting the reliability of mortality statistics for rheumatoid arthritis.

Physicians' amount of diagnostic information and the adequacy of the causal sequence(s) on death certificates involving rheumatoid arthritis (RA) were investigated. Physicians' reporting was compared with the Swedish National Central Bureau of Statistics' (NCBS) registration of the causal conditions, particularly the underlying cause of death. All Swedish RA death certificates for the years 1971 and 1975 were studied. A total of 1224 such certificates were identified. The causal sequences were inadequate in 35% of the certificates, 37% in 1971 and 33% in 1975. Ten types of inadequate sequences were identified. The NCBS rejected the underlying cause of death in 56% of the inadequate sequences and in 52% of the adequate sequences. When the whole sequence leading directly to death was described by only a single diagnosis, 374 (31%) of the cases, this diagnosis was rejected by the NCBS in 54% of the certificates from 1971 and 75% from 1975. More than one diagnosis on each line of the causal-sequence-description appeared on 28% of the certificates. The total number of diagnoses on each certificate did not, however, exceed the NCBS' registration capacity (up to seven diagnoses) in more than 1.6% of the 1224 cases. Thus, the major problem in the NCBS' data collecting process was not how to sort out excessive diagnostic information, but to record properly the causal classification of the conditions, and to interpret the physicians' account of the underlying cause of death.

Arthritis, Rheumatoid↗

PubMed2006

Making sense of discourse: an fMRI study of causal inferencing across sentences.

To build up coherence between sentences (comprehend discourse), we must draw inferences, i.e. activate and integrate information that is not actually stated. We used event-related fMRI to determine the localization and extent of brain activity mediating causal inferencing across short, three-sentence scenarios. Participants read and made causal coherence judgments to sentences that were highly causally related, intermediately related or unrelated to their preceding two-sentence contexts. The highly related and intermediately related scenarios were matched in terms of semantic similarities between their individual component words. A pre-rating study established that causal inferences were generated to the intermediately related but not to the highly related or unrelated scenarios. In the scanner, sentences that were intermediately related (relative to highly related or unrelated) to their preceding contexts were associated with longer judgment reaction times and sustained increases in hemodynamic activity within left lateral temporal/inferior parietal/prefrontal cortices, the right inferior prefrontal gyrus and bilateral superior medial prefrontal cortices. In contrast, sentences that were unrelated (relative to highly related) to their preceding contexts were associated with only transient increases in activity (at, but not after, the peak of the hemodynamic response) within the right lateral temporal cortex and the right inferior prefrontal gyrus. These data suggest that, to make sense of discourse, we activate a large bilateral cortical network in response to what is not explicitly stated. We suggest that this network reflects the activation, retrieval and integration of information from long-term semantic memory into incoming discourse structure during causal inferencing.

Adult↗

PubMed2003

Models of causation and the semantics of causal verbs.

This research examines the relationship between the concept of CAUSE as it is characterized in psychological models of causation and the meaning of causal verbs, such as the verb cause itself. According to focal set models of causation (; ), the concept of CAUSE should be more similar to the concepts of ENABLE and PREVENT than either is to each other. According to a model based on theory of force dynamics, the force dynamic model, the concepts of CAUSE, ENABLE, and PREVENT should be roughly equally similar to one another. The relationship between these predictions and the meaning of causal verbs was examined by having participants sort causal verbs and rate them with respect to the dimensions specified by the two models. The results from five experiments indicated that the force dynamic model provides a better account of the meaning of causal verbs than do focal set models of causation. Implications for causal inference and induction are discussed.

Humans↗