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PubMedDate not supplied

Using path analysis to examine causal relationships among balanced scorecard performance indicators for general hospitals: the case of a public hospital system in Taiwan.

Examining whether the causal relationships among the performance indicators of the balanced scorecard (BSC) framework exist in hospitals is the aim of this article. Data were collected from all twenty-one general hospitals in a public hospital system and their supervising agency for the 3-year period, 2000-2002. The results of the path analyses identified significant causal relationships among four perspectives in the BSC model. We also verified the relationships among indicators within each perspective, some of which varied as time changed. We conclude that hospital administrators can use path analysis to help them identify and manage leading indicators when adopting the BSC model. However, they should also validate causal relationships between leading and lagging indicators periodically because the management environment changes constantly.

Delivery of Health Care↗

PubMed2004

Evidence for a probable causal relationship between tretinoin, acitretin, and etretinate and intracranial hypertension.

With the recognition that vitamin A and isotretinoin may cause intracranial hypertension, the authors reviewed 331 case reports of ocular side effects associated with the three other marketed retinoids: tretinoin, acitretin, and etretinate. The reports were drawn from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization (WHO), the Food and Drug Administration, and medical journals between 1979 and 2003. There were 21 cases of intracranial hypertension associated with these three retinoids, leading to an inference that they are probably causally related to intracranial hypertension by WHO criteria. The lack of positive rechallenge data precludes the inference of a definite causal relationship to intracranial hypertension by WHO criteria. The inference of an independent causal role of these retinoids is further cautioned by the fact that six patients were concurrently using tetracycline or minocycline. Even so, the data suggest that all retinoids may, in rare instances, cause intracranial hypertension.

Acitretin↗

PubMedDate not supplied

Toward a causal model of cardiovascular responses to stress and the development of cardiovascular disease.

OBJECTIVE: Cardiovascular reactivity is hypothesized to mediate the relationship between stress and cardiovascular disease. We describe three considerations that are crucial for a causal model of cardiovascular responses to stress: the need for laboratory-life generalizability, the role of interactions between environmental exposures and individual response predispositions, and the importance of the duration of both stressor exposure and cardiovascular responding. METHODS: We illustrate current understanding of stress-cardiovascular disease relationships with examples from the human and animal psychophysiology, epidemiology, and genetics literature. RESULTS: In a causal model of reactivity, the usefulness of laboratory assessment rests on the assumption that laboratory-based cardiovascular reactivity predicts responses in the natural environment. We find only limited generalizability and suggest that cardiovascular responses to stress can be better understood when examined in the natural environment. The interaction of individual response predispositions and stressor exposures contributes to the development and progression of cardiovascular disease; stress-disease relationships could therefore be better understood if predispositions and exposures were assessed simultaneously in interactive models. Cardiovascular responses to stress are likely to be most deleterious when responses are prolonged. Responses may vary in their magnitude, frequency, and duration; however, reactivity captures only response magnitude. The assessment of anticipatory and recovery measures, with response magnitude, may therefore lead to a more useful model of the stress-disease relationship. CONCLUSIONS: A causal model of cardiovascular responses to stress should generalize to the real world, assess interactions between individual predispositions and environmental exposures, and focus on sustained pathogenic exposures and responses.

Adolescent↗

PubMed2024

A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined genome-wide association studies of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD. APPROACH AND RESULTS: We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1 , TNKS , LYPLAL1 , and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD. CONCLUSIONS: Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.

Humans↗

PubMed2025

Assessing the causal association between celiac disease and Alzheimer disease and frontotemporal dementia: A bidirectional Mendelian randomization approach.

This study aimed to investigate the bidirectional causal relationship between celiac disease (CD) and the risk of Alzheimer disease (AD) or frontotemporal dementia (FTD) using Mendelian randomization (MR), in order to clarify prior inconsistent findings. We analyzed summary-level genome-wide association study (GWAS) data for CD, AD, and FTD. Single-nucleotide polymorphisms (SNPs) strongly associated with each condition were selected as genetic instruments. MR analysis was conducted in 2 directions: from CD to AD/FTD and from AD/FTD to CD. Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) was used to detect and correct for pleiotropy, and Cochran Q assessed heterogeneity. Leave-one-out and Mendelian Randomization-Egger (MR-Egger) regression sensitivity analyses were performed to evaluate robustness. No evidence of a causal effect was found between CD and either AD or FTD in either direction (P > .05). Similarly, genetic liability to AD or FTD did not increase the risk of CD. Sensitivity analyses supported the robustness of the results, showing no pleiotropy or heterogeneity. Our findings suggest that CD is not causally linked to the development of AD or FTD. While shared genetic factors or comorbidities may exist, the association is likely noncausal, and other mechanisms of cognitive decline in CD patients warrant further study.

Humans↗

PubMed2026

Deciphering miRNA-mediated genetic architecture of immune cell subsets in hypertrophic scars and keloids: A 2-step Mendelian randomization study unveiling causal associations.

This study aimed to investigate the potential causal roles of specific circulating microRNAs (miRNAs) and immune cell subsets in the pathogenesis of hypertrophic scars and keloids using a 2-step Mendelian randomization framework. We employed a 2-sample Mendelian randomization approach to evaluate the causal relationships between miRNAs, immune cell genotypes, and scar phenotypes. The analysis integrated miRNA expression quantitative trait loci, immune cell genome-wide association studies, and scar datasets. A 2-step mediation analysis was conducted to assess the indirect effects of miRNAs on scars through immune cell genotypes, using inverse variance weighted methods and complementary sensitivity analyses to ensure robustness. Our analysis identified significant associations between specific miRNAs and scar phenotypes. Notably, miR-6887-5p exhibited a total effect on keloid formation risk (β = 0.324, 95% confidence interval [CI]: 0.073-0.576) and a direct effect (β = 0.283, 95% CI: 0.027, 0.538), with a marginally significant mediation effect through B-cell activating factor receptor on CD20- CD38- B cells (β = 0.042, 95% CI: -0.001, 0.084, P = .047). For hypertrophic scars, miR-345-5p demonstrated a significant total effect (β = -0.501, 95% CI: -0.903, -0.099) and direct effect (β = -0.469, 95% CI: -0.872, -0.066), with a significant mediation effect through CD28+ CD45RA- CD8dim T cell percentage (β = -0.032, 95% CI: -0.062, -0.002, P = .034). miR-4801 showed a significant total effect (β = -0.246, 95% CI: -0.429, -0.064) and direct effect (β = -0.218, 95% CI: -0.402, -0.033), with a marginally significant mediation effect through T cell absolute count (β = -0.028, 95% CI: -0.057, -0.000, P = .043). These findings highlight the interplay between miRNAs and immune cell subsets in scar pathogenesis. This study provides preliminary evidence for the causal roles of specific miRNAs and immune cell subsets in scar formation, emphasizing the potential of miRNA-immune cell axes as therapeutic targets. While the identified associations offer important insights into the molecular mechanisms of scar heterogeneity, further validation through mechanistic studies and clinical trials is necessary to translate these genetic insights into clinical interventions.

Humans↗

PubMed2026

Causal effect of chloride intracellular channel protein 5 on chronic periodontitis: A Mendelian randomization study.

This study aimed to evaluate the potential causal effect of chloride intracellular channel protein 5 (CLIC5) on the risk of chronic periodontitis (CP) using a Mendelian randomization (MR) approach. MR analysis was conducted utilizing publicly available summary statistics from genome-wide association studies summary statistics for CLIC5 and CP. Multiple MR methods, including inverse variance weighted, MR Egger, weighted median and weighted mode, were employed to estimate the causal effects. Sensitivity analyses, comprising leave-one-out and heterogeneity assessments were performed to evaluate the robustness of our findings. This MR analysis consistently revealed a negative association between CLIC5 and CP, with statistical significance achieved using the inverse variance weighted and weighted median methods. The concordant effect estimates obtained from all methodological approaches collectively indicated a potential protective effect of CLIC5 against CP. The sensitivity analyses further confirmed the robustness of these findings. This study provides genetic evidence suggesting a potential causal association between increased CLIC5 levels and decreased risk of CP. These findings augment the existing literature implicating chloride channel proteins in modulating the inflammatory processes pertinent to periodontal health. Further investigation is warranted to decipher the underlying biological mechanisms and to explore the potential of CLIC5 as a therapeutic target for CP.

Chloride Channels↗

PubMed2026

Investigating the causal role of smoking in gout: A triangulation approach combining NHANES data, genetic correlation, and Mendelian randomization.

The relationship between smoking and the development of gout is not well understood. To address this, we adopted a triangulation framework that integrates observational analysis, genetic correlation estimation, and two-sample Mendelian randomization (MR) to examine whether smoking confers a causal risk for gout. We first performed a cross-sectional analysis using information for 13,626 participants from the National Health and Nutrition Examination Survey between 2013 and 2018. The association of smoking with gout was subsequently assessed through logistic regression models. We next investigated the extent of shared genetic factors between smoking phenotypes and gout. We were able to demonstrate this using the linkage disequilibrium score regression applied to genome-wide association study data of European ancestry. Finally, to verify the causality of our relationship, we carried out a two-sample MR analysis. We selected the inverse-variance weighted (IVW) method and confirmed the consistency of using the IVW method with other statistical methods, including weighted median, weighted mode, and simple mode, as well as MR-Egger regression. We performed sensitivity analyses to investigate the heterogeneity of the hypothesis and stability of the data. Our findings based on National Health and Nutrition Examination Survey data reveal that there is a strong positive association between smoking and the risk of gout (odds ratio [OR] = 1.94, 95% confidence interval [CI] = 1.48-2.55, P < .001). This association persisted after confounding adjustments (OR = 1.41, 95% CI = 1.04-1.91, P = .027). In the subgroup analyses, former smokers and current smokers of 10 to 20 cigarettes per day had a substantially increased risk. Post-linkage disequilibrium score regression analysis revealed that the significantly positive genetic correlations of smoking initiation and lifetime smoking index with gout risk were both significantly positive. Additional evidence for causality is presented by MR. Genetic prediction of smoking initiation statistically increases gout risk (IVW OR = 1.55, 95% CI = 1.26-1.90, P = 3.17 × 10-5). A much stronger association is evident for lifetime smoking index (IVW OR = 1.99, 95% CI = 1.44-2.76, P = 3.24 × 10-5). These findings are the same with or without heterogeneity by sensitivity analysis. In light of our integrated analysis, smoking is a causative factor for gout. This suggests that public health interventions like anti-smoking campaigns might reduce gout incidence.

Humans↗

PubMed2025

Causality between telomere length and breast diseases: a two-sample bidirectional Mendelian randomization study.

BACKGROUND: The relationship between telomere length and breast diseases remains unclear, with conflicting evidence for breast cancer. Using an innovative genetic approach, we were the first to comprehensively assess their bidirectional causal relationship. METHODS: Telomere length, breast cancer, benign neoplasm of breast, and breast inflammation were extracted from the genome-wide Association study (GWAS) database as the basis for large-scale population studies. The interaction of telomere length and breast diseases as exposure and outcome factors was analyzed by Mendelian randomization (MR). RESULTS: When telomere length was used as an exposure factor and breast diseases as an outcome, the P value of MR was less than 0.05. Breast cancer (odds ratio (OR) = 1.130, 95% confidence interval (CI) = 1.047-1.219, P = 0.0016), benign neoplasm of breast (OR = 1.002, 95%CI = 1.001-1.004, P = 0.0007) and breast inflammation (OR = 1.487, 95%CI = 1.008-2.191, P = 0.0453). When breast diseases were taken as an exposure factor and telomere length was taken as an outcome, the P value of MR between breast cancer, benign neoplasm of breast, and telomere length was greater than 0.05, and breast inflammation could not be calculated by MR. CONCLUSION: Telomere length is a risk factor for breast diseases, and longer telomeres increase the risk of breast cancer, benign neoplasm of breast, and breast inflammation. However, the reverse study showed no causal association between breast cancer, benign neoplasm of breast and telomere length, and the causal association between breast inflammation and telomere length was not clear. Moreover, further studies are needed to validate our findings in non-European populations.

Mendelian randomization↗

PubMed2023

Pervasive correlations between causal disease effects of proximal SNPs vary with functional annotations and implicate stabilizing selection.

The genetic architecture of human diseases and complex traits has been extensively studied, but little is known about the relationship of causal disease effect sizes between proximal SNPs, which have largely been assumed to be independent. We introduce a new method, LD SNP-pair effect correlation regression (LDSPEC), to estimate the correlation of causal disease effect sizes of derived alleles between proximal SNPs, depending on their allele frequencies, LD, and functional annotations; LDSPEC produced robust estimates in simulations across various genetic architectures. We applied LDSPEC to 70 diseases and complex traits from the UK Biobank (average N=306K), meta-analyzing results across diseases/traits. We detected significantly nonzero effect correlations for proximal SNP pairs (e.g., -0.37±0.09 for low-frequency positive-LD 0-100bp SNP pairs) that decayed with distance (e.g., -0.07±0.01 for low-frequency positive-LD 1-10kb), varied with allele frequency (e.g., -0.15±0.04 for common positive-LD 0-100bp), and varied with LD between SNPs (e.g., +0.12±0.05 for common negative-LD 0-100bp) (because we consider derived alleles, positive-LD and negative-LD SNP pairs may yield very different results). We further determined that SNP pairs with shared functions had stronger effect correlations that spanned longer genomic distances, e.g., -0.37±0.08 for low-frequency positive-LD same-gene promoter SNP pairs (average genomic distance of 47kb (due to alternative splicing)) and -0.32±0.04 for low-frequency positive-LD H3K27ac 0-1kb SNP pairs. Consequently, SNP-heritability estimates were substantially smaller than estimates of the sum of causal effect size variances across all SNPs (ratio of 0.87±0.02 across diseases/traits), particularly for certain functional annotations (e.g., 0.78±0.01 for common Super enhancer SNPs)-even though these quantities are widely assumed to be equal. We recapitulated our findings via forward simulations with an evolutionary model involving stabilizing selection, implicating the action of linkage masking, whereby haplotypes containing linked SNPs with opposite effects on disease have reduced effects on fitness and escape negative selection.

Journal Article↗

PubMed2025

Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's and Parkinson's disease using Polygenic Risk Scores and Mendelian Randomization.

INTRODUCTION: Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with AD and PD. We integrate genetic correlation, Polygenic Risk Scores (PRS), and Mendelian Randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWAS) may distort these causal estimates. METHODS: Using GWAS of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the AD Genetics Consortium (N=27,383), and applied MR methods including Latent Heritable Confounder MR (LHC-MR). RESULTS: Across the four mtDNAcn GWAS, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRS analysis showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk. DISCUSSION: Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect.

Alzheimer’s disease↗

PubMed2000

Causal implications of viscous damping in compressible fluid flows

Classically, a compressible, isothermal, viscous fluid is regarded as a mathematical continuum and its motion is governed by the linearized continuity, Navier-Stokes, and state equations. Unfortunately, solutions of this system are of a diffusive nature and hence do not satisfy causality. However, in the case of a half-space of fluid set to motion by a harmonically vibrating plate the classical equation of motion can, under suitable conditions, be approximated by the damped wave equation. Since this equation is hyperbolic, the resulting solutions satisfy causal requirements. In this work the Laplace transform and other analytical and numerical tools are used to investigate this apparent contradiction. To this end the exact solutions, as well as their special and limiting cases, are found and compared for the two models. The effects of the physical parameters on the solutions and associated quantities are also studied. It is shown that propagating wave fronts are only possible under the hyperbolic model and that the concept of phase speed has different meanings in the two formulations. In addition, discontinuities and shock waves are noted and a physical system is modeled under both formulations. Overall, it is shown that the hyperbolic form gives a more realistic description of the physical problem than does the classical theory. Lastly, a simple mechanical analog is given and connections to viscoelastic fluids are noted. In particular, the research presented here supports the notion that linear compressible, isothermal, viscous fluids can, at least in terms of causality, be better characterized as a type of viscoelastic fluid.

Journal Article↗

PubMed2003

Tree networks with causal structure.

A geometry of networks endowed with a causal structure is discussed using the conventional framework of the equilibrium statistical mechanics. The popular growing network models appear as particular causal models. We focus on a class of tree graphs, an analytically solvable case. General formulas are derived, describing the degree distribution, the ancestor-descendant correlation, and the probability that a randomly chosen node lives at a given geodesic distance from the root. It is shown that the Hausdorff dimension d(H) of the causal networks is generically infinite, in contrast to the maximally random trees where it is generically finite.

Journal Article↗

PubMed2003

Causality and double-negative metamaterials.

The causality of waves propagating in a double-negative (DNG) metamaterial (epsilon (r)<0 and mu(r)<0) has been investigated both analytically and numerically. By considering the one-dimensional electromagnetic problem of a pulsed current sheet radiating into a DNG medium, it is shown that causality is maintained in the presence of a negative index of refraction only if the DNG medium is dispersive. A Drude model DNG medium is used in this study. Spectrograms of the wave phenomena in the dispersive DNG medium show that the higher frequency components, which create the leading edge of the electromagnetic signals and see a double positive (DPS) medium (epsilon (r)>0 and mu(r)>0), arrive causally before the negative index effects germinate completely. Comparisons with approximate analytical results demonstrate the presence of the negative index of refraction properties in the continuous wave portion of the signals. This dynamic pulse reshaping between the positive and negative index of refraction wave components causes an apparent delay in the realization of the negative index of refraction properties. Pulse broadening of the signal tails is associated with both dispersion and a larger negative index of refraction seen by the associated wave components.

Journal Article↗

PubMed2004

Radial basis function approach to nonlinear Granger causality of time series.

We consider an extension of Granger causality to nonlinear bivariate time series. In this frame, if the prediction error of the first time series is reduced by including measurements from the second time series, then the second time series is said to have a causal influence on the first one. Not all the nonlinear prediction schemes are suitable to evaluate causality; indeed, not all of them allow one to quantify how much knowledge of the other time series counts to improve prediction error. We present an approach with bivariate time series modeled by a generalization of radial basis functions and show its application to a pair of unidirectionally coupled chaotic maps and to physiological examples.

Adaptation, Physiological↗

PubMed2005

Causality, Stokes' wave equation, and acoustic pulse propagation in a viscous fluid.

Stokes' acoustic wave equation is solved for the impulse response of an isotropic viscous fluid. Two exact integral forms of solution are derived, both of which are causal, predicting a zero response before the source is activated at time t = 0. Moreover, both integral solutions satisfy a stronger causality condition: the pressure pulse is maximally flat, with all its time derivatives identically zero at t = 0, signifying that there is no instantaneous response to the source anywhere in the fluid. A closed-form approximation for each of the two integrals is derived, with distinctly different properties in the two cases, even though the original integrals are equivalent in that they predict identical pulse shapes. One of these approximations, reminiscent of transient solutions that have appeared previously in the literature, is noncausal due to the incorrect representation of high-frequency components in the propagating pulse. In the second approximation, all frequency components are treated correctly, leading to an impulse response that satisfies the strong causality condition, also satisfied by the original integrals, whereby the predicted pressure pulse is zero when t < 0 and maximally flat everywhere in the fluid immediately after t = 0.

Journal Article↗

PubMed2006

Causal cross-spectral analysis of heart rate and blood pressure variability for describing the impairment of the cardiovascular control in neurally mediated syncope.

A causal approach to the calculation of coherence and transfer function between systolic pressure (SP) and RR interval variability was applied in eight patients and eight control subjects during prolonged tilt test for investigating the impairment of cardiovascular control related to neurally mediated syncope. The causal analysis showed a depressed baroreflex regulation in resting patients, with reduced gain and increased latency from SP to RR, and a drop of the baroreflex coupling immediately before syncope. These findings, which were not elicited by traditional cross-spectral analysis, strongly suggest the use of the causal approach for the study of syncope mechanisms.

Adult↗

PubMed2004

The case-only odds ratio as a causal parameter.

In the simplest case-only design, cases of a disease are cross-classified into a 2 x 2 table describing a genotype attribute and exposure to some environmental agent. In some instances, the genetic attribute has described inherited genes; in other instances, it has described mutations, for instance, damage to proto-oncogenes or tumor suppressor genes leading to cancer. Here, the population case-only odds ratio is written as a causal parameter in terms of potential outcomes with and without exposure to the agent. It is shown that the case-only odds ratio makes sense as a causal parameter with inherited genes, but its magnitude does not have a causal interpretation with mutations, although deviations from 1 do provide information. The difference is that the environmental agent certainly did not cause an individual to inherit particular genes, but it may have caused the mutation.

Biometry↗