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Causal attribution and Mill's methods of experimental inquiry: past, present and prospect.

J. S. Mill proposed a set of Methods of Experimental Inquiry that were intended to guide causal inference under every conceivable set of circumstances in which experiments or observations could be carried out. The conceptual and historical relationship between these Methods and modern models of causal attribution is investigated. Mill's work retains contemporary relevance because his insights show how research can progress into presently uncharted waters. Following Mill, it is proposed that people use many different methods of causal attribution, the nature of which remains to be ascertained, and that the conditions that affect choice of method include the need to eliminate alternative causal candidates, whether single or multiple events are to be explained, the use of intervention or experiment as opposed to mere observation, and practical concerns.

Causality↗

Homelessness and drug abuse among young men who have sex with men in New York city: a preliminary epidemiological trajectory.

The objective of this paper is to profile the role of homelessness in drug and sexual risk in a population of young men who have sex with men (YMSM). Data are from a cross-sectional survey collected between 2000 and 2001 in New York City (N = 569). With the goal of examining the import of homelessness in increased risk for the onset of drug and sexual risk, we compare and contrast three subgroups: (1) YMSM with no history of homelessness, (2) YMSM with a past history of homelessness but who were not homeless at the time of the interview, and (3) YMSM who were currently homeless. For each group, we describe the prevalence of a broad range of stressful life events (including foster care and runaway episodes, involvement in the criminal justice system, etc.), as well as selected mental health problems (including past suicide attempts, current depression, and selected help-seeking variables). Additionally, we examine the prevalence of selected drug and sexual risk, including exposure to a broad range of illegal substances, current use of illegal drugs, and prevalence of lifetime exposure to sex work. Finally, we use an event history analysis approach (time-event displays and paired t-test analysis) to examine the timing of negative life experiences and homelessness relative to the onset of drug and sexual risk. High levels of background negative life experiences and manifest mental health distress are seen in all three groups. Both a prior experience of homelessness and currently being homeless are both strongly associated with both higher levels of lifetime exposure to drug and sexual risk as well as higher levels of current drug and sexual risk. Onset of these risks occur earlier in both groups that have had an experience of housing instability (e.g., runaway, foster care, etc.) but are delayed or not present among YMSM with no history of housing instability. Few YMSM had used drug prior to becoming homeless. While causal inferences are subject to the limitations of a cross-sectional design, the findings pose an empirical challenge to the prevailing assumption that prior drug use is a dominant causal factor in YMSM becoming homeless. More broadly, the data illustrate the complexity of factors that must be accounted for, both in advancing our epidemiological understanding of the complexity of homelessness and its relationship to the onset of drug and sexual risk among high risk youth populations.

Adolescent↗

Shared genetic architecture and cellular convergence between female reproductive disorders and pulmonary function: a genome-wide cross-trait analysis.

Female reproductive disorders (FRDs), including polycystic ovary syndrome, endometriosis, uterine leiomyomata, and infertility, have been epidemiologically associated with impaired pulmonary function. However, it remains unclear whether this cross-organ link reflects shared genetic etiology and, if so, which cellular mechanisms mediate it. We performed a systematic genome-wide cross-trait analysis of three FRDs and lung function traits (FEV₁, FVC, FEV₁/FVC) using GWAS summary statistics from individuals of European ancestry, integrating genetic correlation, bidirectional causal inference, pleiotropy mapping, and single-cell enrichment analyses. We identified significant negative genetic correlations between FRDs and lung volume traits, most prominently for FVC (rg range: - 0.077 to - 0.178). Bidirectional causal analyses indicated that FRDs have a detrimental effect on lung volume, with higher FRD genetic liability associated with reduced lung volume. Cross-trait meta-analysis identified 17 pleiotropic variants across 11 loci, with the 19q13.2 (LTBP4) and 12q13.13 (HOXC6/HOXC9) loci showing strong evidence of shared causal variants. Critically, single-cell analyses revealed that shared genetic risk converged on mesenchymal lineages across organs, specifically alveolar adventitial fibroblasts in the lung and stromal/smooth muscle cells in the endometrium. Transcriptome-wide analyses further nominated the estrogen-responsive gene RERG as a convergent gene linking these conditions with lung function. Our study revealed a shared genetic architecture between female reproductive disorders and lung function traits, providing a basis for further mechanistic investigations and potential clinical evaluation. Furthermore, our findings suggest that shared fibroproliferative and hormone-responsive pathways may offer insights into the biological mechanisms underlying these conditions.

Female↗

Is there a causal relationship between resistin levels and bone mineral density, fracture occurrence? A mendelian randomization study.

BACKGROUND: In a great many of observational studies, whether there is a relevance of resistin levels on bone mineral density (BMD) and fracture occurrence has been inconsistently reported, and the causality is unclear. METHODS: We aim to assess the resistin levels on BMD and fracture occurrence within a Mendelian randomization (MR) analysis. Exposure and outcome data were derived from the Integrative Epidemiology Unit (IEU) Open genome wide association studies (GWAS) database. Screening of instrumental variables (IVs) was performed subject to conditions of relevance, exclusivity, and independence. Inverse variance weighting (IVW) was our primary method for MR analysis based on harmonized data. Weighted median and MR-Egger were chosen to evaluate the robustness of the results of IVW. Simultaneously, heterogeneity and horizontal pleiotropy were also assessed and the direction of potential causality was detected by MR Steiger. Multivariable MR (MVMR) analysis was used to identify whether confounding factors affected the reliability of the results. RESULTS: After Bonferroni correction, the results showed a suggestively positive causality between resistin levels and total body BMD (TB-BMD) in European populations over the age of 60 [β(95%CI): 0.093(0.021, 0.165), P = 0.011]. The weighted median [β(95%CI): 0.111(0.067, 0.213), P = 0.035] and MR-Egger [β(95%CI): 0.162(0.025, 0.2983), P = 0.040] results demonstrate the robustness of the IVW results. No presence of pleiotropy or heterogeneity was detected between them. MR Steiger supports the causal inference result and MVMR suggests its direct effect. CONCLUSIONS: In European population older than 60 years, genetically predicted higher levels of resistin were associated with higher TB-BMD. A significant causality between resistin levels on BMD at different sites, fracture in certain parts of the body, and BMD in four different age groups between 0-60 years of age was not found in our study.

Bone Density↗

Asthma.

From an epidemiological point of view four issues are briefly emphasized here: the definition of asthma, time trends and regional differences, and risk factors for asthma. Furthermore, I will focus upon a few aspects regarding the relation between exercise and asthma. The definition of asthma has presented problems for those involved in studying the disease in general populations, where the estimates rely solely on reported asthma and respiratory symptoms. A standardized questionnaire does not fully overcome differences in languages and interpretations of the concepts of asthma and wheeze over time and in different communities. Although the belief of an upward trend of childhood asthma seems to be widely accepted, studies with the proper methodology to investigate this issue are scarce. The prevalence of asthma varies within and between countries. There is no clear urban rural gradient, and the prevalence of atopy appears to be higher in western than in eastern Europe. Amazingly little is still known about genetic and environmental factors that are causally related to the manifestation of allergic disorders in previously asymptomatic individuals. The effect of exercise on asthma may be many-sided. Children with asthma can actively take part in sport. However, to what extent extensive exercise may affect the occurrence of bronchial responsiveness is unclear, and among athletes exercise may be a risk factor for the development of "athlete's asthma". In conclusion, epidemiological studies have to date not reached their potential due to the lack of longitudinal studies including objective measures of exposures and health outcomes. Causal inference is limited, and further studies designed to answer specific research questions are needed.

Asthma↗

On the origin of Hill's causal criteria.

The rules to assess causation formulated by the eighteenth century Scottish philosopher David Hume are compared to Sir Austin Bradford Hill's causal criteria. The strength of the analogy between Hume's rules and Hill's causal criteria suggests that, irrespective of whether Hume's work was known to Hill or Hill's predecessors, Hume's thinking expresses a point of view still widely shared by contemporary epidemiologists. The lack of systematic experimental proof to causal inferences in epidemiology may explain the analogy of Hume's and Hill's, as opposed to Popper's, logic.

Causality↗

CAUSAL artificial intelligence and data-driven decision intelligence in personalized medicine: a review of healthcare informatics systems.

This review examines the integration of causal artificial intelligence (AI) and data-driven decision intelligence within healthcare informatics systems to advance personalized medicine and clinical decision-making. A narrative review methodology was employed, synthesizing interdisciplinary literature from major databases, including PubMed, Scopus, Web of Science, IEEE Xplore, and ScienceDirect. Studies focusing on causal inference, decision intelligence, and healthcare informatics applications in personalized medicine were included. Data were extracted on methodological approaches, healthcare settings, analytical techniques, and clinical applications, followed by thematic synthesis. Findings indicate that causal AI enhances clinical decision support by enabling estimation of treatment effects and simulation of intervention outcomes at the individual patient level. Integration of multimodal health data such as electronic health records, genomic data, and real-time monitoring improves prediction accuracy and supports tailored treatment strategies. Additionally, causal models improve interpretability, fostering clinician trust and facilitating transparent decision-making. Robust healthcare informatics infrastructures, including interoperable systems and data warehouses, were identified as critical enablers of causal analytics. Overall, causal AI represents a transformative advancement in healthcare analytics, supporting more informed, individualized, and evidence-based clinical decisions. Its integration within healthcare informatics systems has significant potential to improve patient outcomes and guide the future of intelligent, personalized healthcare delivery.

Precision Medicine↗

Integration of multiple omics reveals key targets and cellular mechanisms for intervention in sarcopenia.

BACKGROUND: Sarcopenia, an age-related syndrome characterized by progressive loss of muscle mass, strength, and function, presents a significant global health burden with limited therapeutic interventions. This study integrates genomic causality, multi-tissue omics, and cellular mediation analyses to identify and prioritize mechanistically grounded therapeutic targets. METHODS: A multi-tiered analytical framework was applied, beginning with two-sample Mendelian randomization (MR) to infer causal relationships between 4907 plasma proteins (cis-pQTLs from 35,559 individuals) and sarcopenia traits in Pan-UK Biobank participants. Bayesian colocalization and transcriptomic validation in human sarcopenia muscle biopsies were employed to prioritize targets. Cellular mediation analysis quantified contributions of immune and stromal cell subtypes to protein-trait pathways using transcriptomic deconvolution. RESULTS: MR identified 1237 plasma proteins causally associated with sarcopenia traits, with six targets (HGFAC, GATM, HMOX2, F2, LMAN2L, HPGDS) validated through colocalization, transcriptomic expression, and sarcopenia-related dysregulation. Cellular mediation revealed immune mechanisms underlying HGFAC's effects, with CD4+ regulatory T cells mediating 3.49 % of its impact on sarcopenia traits. Prothrombin exhibited muscle-protective effects independent of coagulation. CONCLUSION: This study establishes a causal map linking plasma proteins to sarcopenia through immune-stromal interactions. The integration of MR, multi-omics validation, and cellular mediation prioritizes six proteins as actionable targets, supporting repurposing of thrombin inhibitors and development of immunometabolic therapies. The framework bridges genomic causality with cellular pathophysiology, advancing precision strategies for age-related muscle decline.

Humans↗

Investigations of causal pathways between PTSD and drug use disorders.

Although numerous studies have demonstrated an association between PTSD and substance use disorders, little is known about the causal nature of this relationship. In this article, we put forth and test major causal hypotheses. Specific hypotheses to be tested include self-medication of PTSD symptoms, substance users' high risk of exposure to traumatic events, and drug users' increased susceptibility to PTSD following a traumatic exposure. We also examine the possibility of an indirect pathway linking drug use disorders and PTSD via a shared vulnerability. Evidence for these causal hypotheses is evaluated using Hill's criteria for causal inference: strength, consistency, specificity, temporality, gradient, plausibility, coherence, experimental evidence, and analogy. We present data analytic strategies that exploit information about the temporal order of PTSD and drug use disorders to shed light on their causal relationship. Finally, we present findings on the PTSD/drug use disorder association from an epidemiologic study of young adults.

Adult↗

Schizophrenia and bipolar disorder: a comparative analysis of genetic and brain network connectivity.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions with overlapping clinical presentations, genetic risk factors, and brain network dysfunction. Whether alterations in large-scale intrinsic brain networks reflect shared or disorder-specific genetic influences remains poorly understood. Clarifying this distinction is essential for refining etiological models and improving diagnostic precision. METHODS: Genome-wide inferred statistics (GWIS) were applied to decompose the genetic architecture of SCZ and BD into shared and unique components. Using resting-state network (RSN) data from the UK Biobank, functional connectivity (FC) and structural connectivity (SC) were extracted as neuroimaging phenotypes. Causal inference approaches were subsequently employed to infer potential directional relationships between brain network connectivity and each disorder. RESULTS: Analyses revealed both common and distinct patterns of brain network connectivity associated with SCZ and BD. Notably, SC within the default mode network (DMN) exhibited opposing effects across the two disorders, suggesting divergent structural underpinnings despite clinical overlap. Additionally, SC within the limbic network (LN) and frontotemporal control network demonstrated potential causal relationships with both conditions, implicating these circuits astransdiagnostic neural substrates. CONCLUSION: These findings illuminate the shared and disorder-specific genetic and neural architecture underlying SCZ and BD. Integrating genome-wide genetic methods with large-scale neuroimaging data offers a powerful framework for disentangling psychiatric comorbidity and may inform more targeted diagnostic criteria and individualized treatment strategies.

Humans↗

Mendelian Randomization Using a Japanese GWAS Identifies an HLA-Linked Causal Effect of Chronic Hepatitis B on Cholangiocarcinoma Risk.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant cancer that develops in the bile ducts. Its incidence is particularly high in East Asian populations, but the underlying genetic factors remain unclear. To investigate potential risk factors for CCA, we conducted a Mendelian randomization study to infer causality. METHODS: Using large-scale genome-wide association study data from the BioBank Japan resource, we systematically investigated the causal effects of genetic predisposition to seven conditions, chronic hepatitis B (CHB), chronic hepatitis C, autoimmune hepatitis, type 1 diabetes, type 2 diabetes, chronic gastritis, and chronic pancreatitis, on CCA risk. RESULTS: Our analysis reveals a significant association between genetic susceptibility to CHB with a 24% higher likelihood of developing CCA than non-susceptible individuals (Inverse-Variance Weighted Odds Ratio = 1.24, 95% Confidence Interval: 1.08-1.42; p = 0.002). This genetic association is significantly driven by instrumental variables enriched in the immune-regulatory HLA class II region (6p21), suggesting a plausible biological mechanism. For the primary outcome (CCA), statistical significance was assessed across seven exposures at a Bonferroni-corrected threshold (two-sided p<0.0071). Notably, the CHB-CCA association remains significant after correction. This primary finding is strongly supported by comprehensive sensitivity analyses that showed no evidence of confounding by horizontal pleiotropy or heterogeneity. Conversely, no significant causal effects on CCA were identified for the other six conditions. CONCLUSIONS: Our MR analysis supports a causal role of HBV infection in CCA development, highlighting the importance of targeted HBV screening and surveillance.

Female↗

Observational research in rheumatic disorders.

Observational research plays an important role in science. Much of human knowledge, including health knowledge, comes from observations, not experiments. Within medicine, observational studies cover a wide scope that ranges from case reports and case series, to descriptive studies, to analytic observational studies for causal questions. These studies often are complementary; each provides a piece of information that can be synthesized into a description and analysis of a health problem in a way that tests hypotheses and advances medical science and has the potential to lead to interventions that can improve health and quality of life. This article reviews the scope of observational studies, principles of causal inference in observational studies, and various types of observational studies with a focus of their applications in rheumatic disorders.

Causality↗

Calculating control variables with age at onset data to adjust for conditions prior to exposure.

BACKGROUND: When assessing the association between a factor X and a subsequent outcome Y in observational studies, the question that arises is what are the variables to adjust for to reduce bias due to confounding for causal inference on the effect of X on Y. Disregarding such factors is often a source of overestimation because these variables may affect both X and Y. On the other hand, adjustment for such variables can also be a source of underestimation because such variables may be the causal consequence of X and part of the mechanism that leads from X to Y. METHODS: In this paper, we present a simple method to compute control variables in the presence of age at onset data on both X and a set of other variables. Using these age at onset data, control variables are computed that adjust only for conditions that occur prior to X. This strategy can be used in prospective as well as in survival analysis. Our method is motivated by an argument based on the counterfactual model of a causal effect. RESULTS: The procedure is exemplified by examining of the relation between panic attack and the subsequent incidence of MDD. CONCLUSIONS: The results reveal that the adjustment for all other variables, irrespective of their temporal relation to X, can yield a false negative result (despite unconsidered confounders and other sources of bias).

Adolescent↗

[Clinical trials: principles of the method].

Comparative judgement, which is seminal to any kind of science performing measurements, has been applied to clinical reasoning for many centuries. The need for systematizing the observational methods used in medicine in order to draw more reliable inferences about the effects of therapies has been active all along the 19th century. This has resulted in controlled studies which yielded important advances in clinical and therapeutic knowledge, although their designs were not fully satisfactory. Clinical trials have gained their status of "hard science", methodology allowing causal inference, by the end of the 1940s after having adopted the statistical theories developed in the 1930s by Fisher for experimental design in agronomy. A long way has been run since the first controlled randomized trial. However, half a century later, modern clinical trial remains essentially a controlled randomized prospective study using methods to limit potential biases and to establish statistical significance.

Clinical Trials as Topic↗

Critical appraisal of the evidence that dietary fat intake is related to breast cancer risk in humans.

A critical appraisal was undertaken of the evidence that dietary fat intake is related to breast cancer risk by application of the criteria for causal inference proposed by Bradford Hill to the published evidence that relates dietary fat to breast cancer risk in humans. These criteria concern the consistency, strength, and temporal relationships of possible causative associations and also require the existence of a biologic gradient and examine the extent to which the proposed causal association is in keeping with other biological and epidemiological knowledge. The published reports were inconsistent in their ability to detect a significant association between dietary fat and breast cancer risk, correlation studies that examined the effect of fat over large ranges being largely positive, and studies with stronger designs (case-control, cohort) that examined fat intake over much smaller ranges being largely negative. It was postulated that methodologic limitations associated with the design of the latter studies, in particular the small ranges of fat intake examined and inaccuracies in the measurement of fat intake, may have obscured any relationships between dietary fat and breast cancer that did exist. The remaining criteria, with the exception of temporality and epidemiological coherence, were not satisfied. Insufficient evidence existed to conclude a causal association existed between dietary fat and breast cancer risk in humans. A need for further study was identified in several areas, and it was concluded that intervention studies that examined the effect of fat over large ranges were most likely to yield the information required to determine whether dietary fat intake was causally related to breast cancer risk.

Animals↗

Integrative Genomic and Functional Investigation of the Multi-Layered Genetic Architecture Between Anorexia Nervosa and Bone Loss.

OBJECTIVE: Bone loss is a severe and often irreversible complication of anorexia nervosa (AN), yet the genetic mechanisms underlying this comorbidity remain underexplored. This study focuses on constructing a comprehensive genetic architecture between AN and estimated calcaneal bone mineral density (eBMD). METHOD: We applied an integrative framework incorporating genetic correlation, pleiotropic association, and causal inference across single-variant, multi-variant, and gene expression levels. Functional validation was conducted in&#xa0;vitro to investigate the biological role of the key candidate gene. RESULTS: Local genetic correlation analysis identified significant signals at 8p21.2 and 10q26.3, despite the lack of significant global correlation. Mendelian randomization analysis pointed to a suggestive negative causal effect of genetically predisposed AN on eBMD. Extensive pleiotropic signals were detected, particularly at 3p21.31 and 10q26.3, loci enriched with genes associated with both traits. Notably, we identified a novel pleiotropic signal near NCAM1 at 11q23.2, which was supported by multi-layered genetic evidence and confirmed through in&#xa0;vitro functional experiments. NCAM1, a well-established neural-associated gene, promoted osteoclastic differentiation and bone resorption when overexpressed in osteoclast precursor cells, indicating that NCAM1 possesses distinct functional roles in both neural and skeletal tissues. DISCUSSION: This study constructs a comprehensive genetic architecture underlying AN and eBMD and highlights NCAM1 as a key pleiotropic gene.

anorexia nervosa↗

Uncovering metabolite-immune interactions in the pathogenesis of psoriatic arthritis: A 2-sample Mendelian randomization study.

PsA is a chronic inflammatory joint condition associated with psoriasis, and its underlying mechanisms are not fully elucidated. Serum metabolites, as direct reflections of metabolic status, may influence disease progression by regulating immune cell function; however, the causal relationships and specific pathways require further investigation. The present investigation utilized a 2-sample bidirectional MR methodology, leveraging extensive pooled GWAS data to thoroughly evaluate the causal relationships between 1440 serum metabolites and PsA. Additionally, mediation MR analysis was performed to explore the possible mediating effects of 731 immune cell characteristics. In the primary analysis, inverse-variance weighted was employed, and this was further supported by various sensitivity analyses to confirm the reliability of the findings. The genetic method to infer causality analysis revealed significant positive causal associations between 10 serum metabolites and PsA risk, with quinolinate levels demonstrating the most significant correlation (OR&#x2005;=&#x2005;1.56, 95% CI: 1.26-1.93); while 4 metabolites (e.g., citrate levels, OR&#x2005;=&#x2005;0.74, 95% CI: 0.61-0.89) exhibited protective effects. Regarding immune cells, 6 cellular features (e.g., CD20 on B cells) were positively correlated with disease risk, whereas 5 features (primarily HLA-DR expression on monocyte subsets) showed negative correlations. Mediation analysis identified 3 significant pathways,the percentage of the effect explained by the mediator: N6,N6,N6-trimethyllysine levels mediated via B cells (CD20 on IgD+ CD38br), with a proportion of 33.2%; 1-stearoyl-2-docosahexaenoyl-GPE (18:0/22:6) levels mediated through monocytes (HLA-DR on CD14- CD16-) with a 32.0% proportion; the unknown metabolite X-24736 also mediated 42.1% of the protective effect via the same monocyte phenotype. This study revealed that elevated amino acid-related metabolites and glycerophospholipids significantly increase PsA risk through immune cell effects. These are closely associated with PsA pathogenesis and may serve as potential biomarkers. The novel findings underscore metabolic-immune interactions as targets for biomarkers and therapies in PsA, advancing personalized medicine.

Humans↗

Unraveling causal links between chronic rhinosinusitis and peripheral artery diseases: insights from genetic correlations through genome-wide association studies.

OBJECTIVES: Chronic Rhinosinusitis (CRS) shares epidemiological links with Cardiovascular Diseases (CVDs), however, their shared genetic basis remains unclear. We hypothesized that pleiotropic genetic variants underlie CRS-CVDs links via distinct biological pathways. METHODS: Using large-scale GWAS data from European-ancestry individuals, we assessed global and local genetic correlations. We applied Genomic Structural Equation Modeling (Genomic SEM) to dissect shared genetic architecture, performed bidirectional Mendelian Randomization (MR) to infer causality, and conducted cis-eQTL colocalization to identify shared genetic signals. Finally, in vitro endothelial models (HUVECs) validated the functional dynamics of candidate genes under CRS-mimicking inflammatory stress. RESULTS: CRS showed significant genetic correlations with multiple CVDs. Genomic SEM revealed a latent factor structuring shared genetic risk through three pathways: artery diseases, myocardial diseases, and heart failure. Local genetic correlations identified significant local genetic correlations specifically between CRS and Peripheral Atherosclerosis (PAS)/Peripheral Artery Disease (PAD) specifically within the chr6: 31.57&#x2012;33.24 Mb locus. MR demonstrated causal effects of CRS on PAD (OR&#x2009;=&#x2009;1.23, p&#x2009;=&#x2009;0.022) and PAS (OR&#x2009;=&#x2009;1.21, p&#x2009;=&#x2009;0.011), but not vice versa. Genetically predicted HLA-DRB1, APOM, and COL11A2 expression conferred protection, while HLA-DQA2 increased risk. Crucially, in vitro validation corroborated these pathogenic trajectories, inflammatory stress significantly downregulated the protective APOM and upregulated the risk-associated HLA-DQA2 alongside pro-atherogenic VCAM-1, while HLA-DRB1 exhibited a compensatory upregulation (p&#x2009;<&#x2009;0.05). CONCLUSION: CRS shares global genetic liability with CVDs, structured through three primary etiological pathways. Causal effects of CRS on peripheral artery diseases are mediated by immune and lipid-related genes within the chr6 locus, revealing divergent pleiotropic mechanisms. Our integrated genetic and in vitro evidence provides a mechanistic framework wherein chronic mucosal inflammation contributes to systemic endothelial vulnerability, thereby highlighting candidate targets for mechanism-directed therapy.

Humans↗