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PubMed1988

Agenesis of the corpus callosum and schizophrenia: a case report.

Clinical, radiological and neuropsychological findings in the first reported case of schizophrenia with complete agenesis of the corpus callosum are described. Although causal inferences were made difficult by the co-existence of a left frontotemporal cyst and a family history of affective disorder, some theories of the role of callosal dysfunction in schizophrenia require revision in the light of this case.

Agenesis of Corpus Callosum↗

PubMed2026

Adolescent depression as a systemic multimorbidity catalyst: integrated genetic and metabolic pathway analysis.

BACKGROUND: Although adolescent depression has been linked to individual chronic conditions, its broader role in shaping multimorbidity risk remains understudied. METHODS: A total of 87,562 UK Biobank participants were included, of whom 18,851 had documented adolescent depression. Cox proportional hazards models were applied to evaluate associations between adolescent depression and 24 chronic diseases, followed by stratified analyses by sex and age. Two-sample Mendelian randomization (MR) was then conducted to infer causality for diseases showing significant associations. Genomic colocalization analyses were performed using relevant GWAS data to identify shared causal variants. Mediation analyses were performed to detect possible mediating factors, including the frailty index, KDM biological age acceleration, allostatic load and 30 circulating biomarkers. RESULTS: Adolescent depression was associated with elevated risk for 12 chronic diseases, with strongest associations for hypothyroidism (HR = 1.29 [1.18-1.42]), diabetes (HR = 1.25 [1.13-1.38]) and chronic obstructive pulmonary disease (COPD) (HR = 1.74 [1.50-2.01]). Risks were notably higher among females and younger adults. MR confirmed likely causal relationships for hypothyroidism (OR = 1.45 [1.03-2.05]), diabetes (OR = 1.01 [1.01-1.02]) and COPD (OR = 1.04 [1.02-1.06]). Genomic colocalization revealed a shared genetic signal at the CDSN/PSORS1C1 locus between adolescent depression and hypothyroidism. Mediation analyses revealed disease-specific pathways: creatinine for hypothyroidism, testosterone for diabetes, KDM biological ageing for COPD and frailty index across all three conditions. CONCLUSIONS: Adolescent depression confers systemic vulnerability through genetic and metabolic mechanisms, with amplified risks in females and individuals aged ≤55 years. These findings support early, integrated interventions to mitigate long-term multimorbidity.

Humans↗

PubMed2000

A Rationale for Using Synthetic Designs in Medical Education Research.

The extent to which the results of a study can be attributed to the intervention under investigation (i.e., internal validity) is an important consideration in interpreting study findings. There are many threats to the internal validity of designs frequently used in medical education research. Synthetic designs, which involve the integration of two or more weak designs, or the addition of design elements, may afford investigators greater control over confounding variables in medical education research. A rationale for using synthetic designs is presented and two examples of their use in medical education settings are examined. The concluding proposition is that synthetic designs allow investigators flexibility in planning research that is feasible in medical education settings. In addition, they may permit stronger causal inferences between interventions and results than traditional research designs.

Journal Article↗

PubMed1998

Degree of somatoform and psychological dissociation in dissociative disorder is correlated with reported trauma.

In this study, the prevalence and severity of traumatic experiences as reported by patients with dissociative disorders and with other DSM-IV psychiatric diagnoses were compared. Furthermore, the predictive value of emotional, physical, and sexual trauma with respect to somatoform and psychological dissociation was analyzed. In contrast with comparison patients, dissociative disorder patients reported severe and multifaceted traumatization. Physical and sexual trauma predicted somatoform dissociation, sexual trauma predicted psychological dissociation as well. According to the memories of the dissociative disorder patients, this abuse occurred in an emotionally neglectful and abusive social context. Pathological dissociation was best predicted by early onset of reported intense, chronic and multiple traumatization. Methodological limitations restricting causal inferences between reported trauma and dissociation are discussed.

Adolescent↗

PubMed1996

The efficacy and effectiveness of psychotherapy relative to medications.

A recent survey by Consumer Reports (1994) found that people who received psychotherapy were generally pleased with their experience and that their satisfaction was unrelated to the type of treatment or the addition of medications. M.E.P. Seligman (1995) argued that these findings demonstrate the value of psychotherapy and suggested that such survey methodologies may be superior to randomized clinical trials in this regard because they study what occurs in actual clinical practice. Although such approaches provide important information, they are no substitute for controlled clinical trials when it comes to drawing causal inferences. However, the study does highlight the importance of defining outcome in the broadest possible fashion and of addressing the external validity of the findings obtained. Attention to such considerations has implications for the relative value of drugs and psychotherapy.

Combined Modality Therapy↗

PubMed1989

Characterizing life events as risk factors for depression: the role of fateful loss events.

Empirical associations between life events and health are often weak, in part because event exposure measures may group together very different kinds of experiences within a single event category. Attempts to refine the measures (by using respondents' subjective appraisals of event stressfulness or by taking into consideration situational and personal factors that influence the contextual threat of the events) may strengthen the association, but they cloud the clarity of any causal inference by confounding the measure with extraneous variation. Instead, the use of descriptive information about what actually happened before, during, and after each event is recommended to define exposure to potent, fateful life events. In a comparison of 96 patients with major depression and 404 community residents with no apparent depression, the odds that a person would have experienced one or more events meeting criteria for fatefulness and disruptiveness was 2.5 times greater in the depressed group.

Adult↗

PubMed1999

The temporal relation of adherence and alliance to symptom change in cognitive therapy for depression.

This study attempted to replicate an earlier study (R. J. DeRubeis & M. Feeley, 1990) of the prediction of symptom change from process variables in cognitive therapy for depressed outpatients. Measures of in-session therapist behavior and therapist-patient interactions were correlated with prior and subsequent symptom change. One of the positive findings was confirmed, but the other received only marginal support. A "concrete" subset of theory-specified therapist actions, measured early in treatment, predicted subsequent change in depression. The therapeutic alliance was predicted by prior symptom change in 1 of the 2 later assessments, but only at a trend level. Several negative findings were similar to those obtained in the earlier study. Specifically, the alliance, an "abstract" subset of theory-specified therapist actions, and facilitative conditions did not predict subsequent change. Implications for causal inferences in psychotherapy process research are discussed.

Adult↗

PubMed2001

Concluding causation from correlation: comment on Burns and Spangler (2000).

This commentary critiques the study conducted by D. D. Burns and D. Spangler (2000) in which the relationship between homework compliance and therapy outcome was estimated using structural equation modeling (SEM). Although the authors of the commentary advocate the use of SEM, they suggest greater caution in the indiscriminate endorsement of a causal relationship based on (a) correlational data and (b) retrospective accounts of the main predictor variable within a cross-sectional design. This discussion also highlights a need to address the issue of therapist competence in homework administration. The results of Burns and Spangler's report are consistent with existing empirical evidence suggesting that compliance with homework facilitates therapeutic outcome. However, the gold standard for determining causal inferences rests on prospective, experimental research rather than on retrospective, correlational models.

Humans↗

PubMed1975

Sociocultural context of individual creativity: a transhistorical time-series analysis.

Hypotheses were stated which specify individual creativity as a function of developmental and productive period variables. It was then argued that these hypotheses could be better tested by examining generational fluctuations in creativity. Information from cultural and political archival sources was thus aggregated to form time series spanning 127 generations of European history. Data quality checks, control variables, data transformations, time-lagged comparisons, and trend analyses were used to improve the validity of the causal inferences. While the results varied according to the type of creativity (discursive or presentational) and the degree of achieved eminence, creative development was found to be affected by the following: (a) role model availability, (b) political fragmentation, (c) imperial instability, and (d) political instability.

Achievement↗

PubMed1986

Personality, coping, and family resources in stress resistance: a longitudinal analysis.

Earlier cross-sectional analyses have made causal inferences about stress-resistance variables problematic. This study used a longitudinal analysis where stress-resistance factors in the areas of personality, coping, and family support assessed at an initial testing were used to predict psychological and physical adjustment one year later, controlling for initial adjustment. The study involved a survey of 245 men and 248 women in randomly selected families in the San Francisco Bay area. Findings demonstrated that feelings of self-confidence, an easy-going disposition, a disinclination to use avoidance coping, and the availability of family support operate jointly to protect individuals from negative psychological consequences of life stress. For women the stress-resistance index also predicted psychosomatic complaints experienced one year after initial testing.

Adaptation, Psychological↗

PubMed1990

A probabilistic contrast model of causal induction.

Deviations from the predictions of covariational models of causal attribution have often been reported in the literature. These include a bias against using consensus information, a bias toward attributing effects to a person, and a tendency to make a variety of unpredicted conjunctive attributions. It is contended that these deviations, rather than representing irrational biases, could be due to (a) unspecified information over which causal inferences are computed and (b) the questionable normativeness of the models against which these deviations have been measured. A probabilistic extension of Kelley's analysis-of-variance analogy is proposed. An experiment was performed to assess the above biases and evaluate the proposed model against competing ones. The results indicate that the inference process is unbiased.

Adult↗

PubMed1992

Externalizing behavior problems and academic underachievement in childhood and adolescence: causal relationships and underlying mechanisms.

Conceptual and measurement issues surrounding externalizing behavior problems and academic underachievement, the strength and specificity of the covariation between these domains, and the viability of explanatory models that link these areas are reviewed. In childhood, inattention and hyperactivity are stronger correlates of academic problems than is aggression; by adolescence, however, antisocial behavior and delinquency are clearly associated with underachievement. Whereas investigations with designs that allow accurate causal inference are scarce, unidirectional paths from 1 domain to the other have received little support. Indeed, the overlap of externalizing problems with cognitive and readiness deficits early in development suggests the influence of antecedent variables. Low socioeconomic status, family adversity, subaverage IQ, language deficits, and neurodevelopmental delay are explored as possible underlying factors.

Adolescent↗

PubMed1997

Counterfactual thinking.

Counterfactuals are mental representations of alternatives to the past and produce consequences that are both beneficial and aversive to the individual. These apparently contradictory effects are integrated in a functionalist model of counterfactual thinking. The author reviews research in support of the assertions that (a) counterfactual thinking is activated automatically in response to negative affect, (b) the content of counterfactuals targets particularly likely causes of misfortune, (c) counterfactuals produce negative affective consequences through a contrast-effect mechanism and positive inferential consequences through a causal-inference mechanism, and (d) the net effect of counterfactual thinking is beneficial.

Anger↗

PubMed2002

Ordinary physical punishment: is it harmful? Comment on Gershoff (2002).

E. T. Gershoff (2002) reviewed processes that might mediate and contexts that might moderate the associations between corporal punishment (CP) and child behaviors and provided an account of the methodological weaknesses of the research reviewed in her meta-analyses. In this examination of Gershoff, the authors argue that the biases and confounds in the meta-analyses further limit any causal inferences that can be drawn concerning the detrimental "effects" of CP on associated child behaviors. The authors suggest that undesirable child outcomes are associated with CP because the construct marks inept harsh parenting and conclude that although the harmful effects of physical abuse and other extreme punishments are clear, a blanket injunction against spanking is not justified by the evidence presented by Gershoff.

Adolescent↗

PubMed2006

Does changing behavioral intentions engender behavior change? A meta-analysis of the experimental evidence.

Numerous theories in social and health psychology assume that intentions cause behaviors. However, most tests of the intention- behavior relation involve correlational studies that preclude causal inferences. In order to determine whether changes in behavioral intention engender behavior change, participants should be assigned randomly to a treatment that significantly increases the strength of respective intentions relative to a control condition, and differences in subsequent behavior should be compared. The present research obtained 47 experimental tests of intention-behavior relations that satisfied these criteria. Meta-analysis showed that a medium-to-large change in intention (d = 0.66) leads to a small-to-medium change in behavior (d = 0.36). The review also identified several conceptual factors, methodological features, and intervention characteristics that moderate intention-behavior consistency.

Attitude↗

PubMed2005

Population structure, differential bias and genomic control in a large-scale, case-control association study.

The main problems in drawing causal inferences from epidemiological case-control studies are confounding by unmeasured extraneous factors, selection bias and differential misclassification of exposure. In genetics the first of these, in the form of population structure, has dominated recent debate. Population structure explained part of the significant +11.2% inflation of test statistics we observed in an analysis of 6,322 nonsynonymous SNPs in 816 cases of type 1 diabetes and 877 population-based controls from Great Britain. The remainder of the inflation resulted from differential bias in genotype scoring between case and control DNA samples, which originated from two laboratories, causing false-positive associations. To avoid excluding SNPs and losing valuable information, we extended the genomic control method by applying a variable downweighting to each SNP.

Adolescent↗

PubMed2026

Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8 + T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.

Humans↗

PubMed2025

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities.

Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank. The genome-wide type 2 diabetes polygenic score associates with 617 proteins, of which 75% also associate with another cardiometabolic score. Partitioned type 2 diabetes scores, which capture distinct disease biology, associate with 342 proteins (20% unique). In this work, we identify key pathways (e.g., complement cascade), potential therapeutic targets (e.g., FAM3D in type 2 diabetes), and biomarkers of diabetic comorbidities (e.g., EFEMP1 and IGFBP2) through causal inference, pathway enrichment, and Cox regression of clinical trial outcomes. Our results are available via an interactive portal ( https://public.cgr.astrazeneca.com/t2d-pgs/v1/ ).

Humans↗