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Results for “instrumental variable assumptions”

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PubMed2025

No More Free Lunch: Challenges to Mendelian Randomization Due to Sample Selection and Complex Methods.

Mendelian randomization (MR) is increasingly used in epidemiological studies to investigate causal relationships. MR depends on 3 fundamental instrumental variable assumptions: relevance, independence, and exclusion restriction. Studies often assume that MR mitigates bias from confounding due to the random allocation of genetic variants at conception. In this perspective, using causal directed acyclic graphs, we discuss several scenarios where biases in MR analyses may arise due to the nature of the data or methods being used. These include (1) collider bias due to the nonrandom selection of participants into study populations used for conducting genome-wide association studies (GWAS), (2) indirect genetic effects arising from population-based GWAS rather than within-family studies, and (3) collider bias due to gene-environment interaction effects on the exposure in nonlinear MR analyses. We provide practical considerations for examining and reducing these biases in MR analyses.

Humans↗

PubMed2026

Novel Insights into Immune Cell Function in Type 2 Diabetes Mediated by Gut Microbiota: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: The role of immune cells in type 2 diabetes mellitus (T2DM) development is well-studied, but their interactions with the gut microbiota and the mediating role in this process remain unclear. METHODS: We analyzed 731 immune cell phenotypes (3,757 Europeans), 473 gut microbiota traits (5,959 Finns), and T2DM data (over 400,000 Finns). Mendelian randomization (MR) was based on three assumptions: the instrumental variable (IV) is associated with exposure, IV is not influenced by confounding, and IV affects the outcome only through exposure. We selected single-nucleotide polymorphisms (SNPs) from genome-wide association studies as instrumental variables (IVs) to infer causal effects in two-sample MR analysis. RESULTS: We identified 36 immune cell phenotypes associated with T2DM, including 29 protective factors and seven risk factors, as well as 10 gut microbiota significantly linked to T2DM, with eight protective factors and two risk factors. MR revealed that five gut microbiota mediated the relationship between immune cells and T2DM. For example, the effects of CD3 on resting Treg (OR: 1.0136), CD3 on CM CD4+ (OR: 1.0180), and CD3 on naive CD4+ cells (OR: 1.0150) in T2DM were found to be partially mediated by the species Bacillus. AYThe corresponding mediation effect proportions were 8.99%, 11.8%, and 11.4%. DISCUSSION: MR analysis identified multiple gut microbiota mediators in the relationship between immune cells and T2DM, addressing previous observational evidence. Limitations included the European ancestry bias, among others. CONCLUSION: This study has highlighted the gut microbiota as a mediator between immune cells and T2DM, offering new insights for its early prevention and intervention.

Diabetes Mellitus, Type 2↗

PubMed2025

Association between NAFLD and liver cancer: A two-sample Mendelian randomization study.

Observational studies suggest an association between nonalcoholic fatty liver disease (NAFLD) and liver cancer, but its causal nature remains unclear. A 2-sample Mendelian randomization (MR) analysis was performed using NAFLD and liver cancer summary statistics from genome-wide association study databases. Instrumental variables satisfying the 3 core MR assumptions were selected. Causal effects were estimated using inverse-variance weighted, MR-Egger, weighted median, and other methods, followed by sensitivity and power analyses. All 4 MR analyses demonstrated a positive causal association between NAFLD and liver cancer risk [odds ratio > 1, inverse-variance weighted P < .001]. Sensitivity analysis indicated no significant level of multiplicity or heterogeneity in the instrumental variables, and individual single nucleotide polymorphisms had no significant impact on the results. However, statistical power was insufficient. This study provides the first MR evidence demonstrating a genetically predicted causal relationship between NAFLD and liver cancer that is consistent across subtypes. Sensitivity analyses confirmed the absence of horizontal pleiotropy or heterogeneity, strengthening the robustness of the findings. These results offer genetic support for early NAFLD intervention to reduce the risk of liver cancer. However, the limited statistical power highlights the need for larger-scale genome-wide association study to identify more and stronger genetic instruments for a more precise quantification of the causal effect of NAFLD on liver cancer risk.

Humans↗

PubMed1975

Variation of energy density in argon laser photocoagulation.

The power density at the retina provided by presently available laser photocoagulators is subject to variation. Three factors contribute to making the retinal image of the laser beam substantially different from the spot size indicated on the selector of the photocoagulator. These are the operator's variable accommodation, the astigmatism introduced by the contact lens, and the depth of focus of the observation system. The assumption that the same setting on the instrument regularly produces the same power density at the retina will lead to errors in comparing lesions. The safest procedure is to start from the threshold in every location.

Argon↗

PubMed1977

Critical evaluation of the Obscure Figures Test as an instrument for measuring "cognitive innovation".

The Obscure Figure Test has been conceptualized by Acker and McReynolds (1965) as a measure of Cognitive Innovation. As a general concept Cognitive Innovation refers to an integration of different kinds of behavioral systems, e.g., creativity and exploratory behavior. Considering recent research about the relationship between curiosity and creativity as well as basic assumptions underlying this test, it is hypothesized that this is an instrument for measuring creativity rather than curiosity. 41 boys and 41 girls ranging from 7 to 10 yr. of age were given a battery of tests of curiosity and creativity. There were significant correlations between Obscure Figures Test and creativity measures. No such relationships were found between obscure figures and curiosity measures. A factor analysis yielded two factors which could be interpreted as "visual exploration" and "creativity", the obscure figures being a marker variable on the latter factor. Results are discussed in terms of the theoretical assumptions underlying the concepts of curiosity, creativity, and Cognitive Innovation. Further implications with respect to the requirements for an operationalization of Cognitive Innovations are mentioned.

Child↗

PubMed1991

Quantal analysis and synaptic efficacy in the CNS.

Quantal analysis of synaptic transmission at connections between neurons in the CNS has provided insights concerning the structural constraints on transmitter release and postsynaptic responsiveness. However, it has proven difficult in many cases to resolve the size and variability of a single quantum or to distinguish clear peaks in amplitude histograms of evoked responses, due in part to the superposition of background instrumental and biological noise. These limitations raise questions about recent attempts to use direct or indirect methods of quantal analysis in order to distinguish between pre- and postsynaptic loci of the modifications underlying long-term potentiation, particularly since the interpretations are model-dependent and the statistical treatments and experimental techniques employed incorporate simplifying assumptions not yet proven.

Animals↗

PubMed1976

[Analogs and models of systemic arterial circulation].

This review article is primarily aimed at those researches using the experimental physiological approach and gives a survey of analogs and models of the systemic arterial blood flow. They are presented in increasing order of complexity in two sections: the "lumped" and the "distributed" parameter models. In the first section a brief description is given of the purely resistive, Windkessel and multi-element analogs with emphasis on their use in physiology for estimating several hemodynamic variables. The distributed parameter models, whose central idea is pulse wave propagation along the arterial tree, are then presented in five categories, using a new classification scheme. These categories are based on four criteria derived from the assumptions used in the formulation of the fluid and wall equations. The most recent non-linear models are treated in more detail with their common properteis as well as their particular contribution emphasized. In conclusion it is noted that the distributed parameter models also begin to be used to evaluate physiological variables in the experimental and clinical context and that this trend can only become more important in view of the advances made in the field of biomedical instrumentation.

Animals↗

PubMed1992

The clinical Swiss army knife. Empirical evidence on the validity of IADL functional status measures.

To encourage the clinical use of functional status measures, tools have been developed that are shorter and easier to administer. This study was conducted to provide empirical evidence concerning the validity of instrumental activities of daily living (IADL) scales. Similar to previous findings, this study found that a 50-item questionnaire was suitable for patient self-completion. This scale also showed good reproducibility over a 2-week period, a unidimensional factor structure, internal consistency, predictable correlations with other health status measures, and the ability to distinguish formal service users from nonusers. On the other hand, the findings also clearly demonstrate that caution is warranted when choosing rating formats and scoring procedures, and when interpreting patient responses. Ratings of difficulty, nonperformance, and assistance received should not be assumed to be interchangeable nor to reflect underlying physical ability. A great deal of sample variability was found when the process validity, or the subjective meanings of these ratings was examined. Scalogram analysis also indicated that the assumption of hierarchical ordering is not justified. Based on these findings, minimal questioning, dichotomous responses categories, and aggregate scores are not recommended for discharge planning or monitoring individual patients.

Activities of Daily Living↗

PubMed2026

Aerobic Fitness and Health-Related Phenotypes: A Two-Stage Phenome-Wide Mendelian Randomization Study.

PURPOSE: We investigated potentially causal associations between genetically predicted aerobic fitness and multiple health phenotypes using a two-stage phenome-wide Mendelian randomization (MR) study. METHODS: Genetically determined aerobic fitness, as operationalized by Cai et al., served as the exposure instrument. We screened 712 health-related phenotypes as outcomes using publicly available European-ancestry genome-wide association studies (GWAS) summary statistics from OpenGWAS (Discovery GWAS n > 5000), prioritizing non-UK Biobank/non-FinnGen datasets for Discovery when available and selecting an independent GWAS for validation. Associations were estimated using the MR-Robust Adjusted Profile Score method, controlled for multiple testing (5% false discovery rate) and unaffected by violations of MR assumptions (directional concordance between discovery and validation; no evidence of horizontal pleiotropy across inverse-variance weighted, MR-Egger, weighted-median, and weighted-mode methods; negative control analysis on hair color). RESULTS: We identified 108 discovery associations, of which 34 remained valid and statistically significant after validation. Higher genetically determined aerobic fitness was associated with lower lacunar stroke risk, lower arterial stiffness, higher heart rate variability, lower diastolic blood pressure, more favorable anthropometric measures, lower use of antidiabetic drugs, lower asthma risk, lower C-reactive protein, higher bone mineral density, favorable liver function biomarkers, favorable platelet-related traits, multiple blood count-derived hematological cell indices and counts, as well as higher years of schooling. Adverse associations were confined to atrial fibrillation, valvular heart disease, and systolic blood pressure. CONCLUSIONS: Genetically determined aerobic fitness is linked to a broad pattern of favorable cardiometabolic, inflammatory, musculoskeletal, respiratory, hepatic, and hematological phenotypes, alongside a narrow set of potential cardiovascular hazards.

Humans↗

PubMed1992

[Common attitudes about the effect of positive and negative mood on task related motivation].

Several theories on emotion and mood have stressed the close relationship between emotion and motivation. However, assumptions on mood contingent motivations have mainly been studied in the field of social behavior, and there are only few studies concerned with mood contingent task motivations, an area in which nit is possible to distinguish between two motivational sets, the deliberative and the implemented mind set. Assuming that positive mood is associated with a stronger task-oriented deliberative mind set, and that negative mood is associated with a stronger self-oriented deliberative mind set, and that implemented mind set should be intrinsically task-oriented during positive mood and instrumentally task-oriented during negative mood. The present paper is concerned with these assumptions from a subjective perspective: The respondents were asked about their lay perceptions of mood influences (positive, elated versus negative, sad mood) on task related motivations. In study I the respondents (N = 40) were asked about their deliberative mind sets during positive versus negative mood and about their general perceptions of mood influences on performance. In study II the respondents (N = 58) were requested to imagine situations which elicit positive, negative or neutral mood, and then to answer questions on deliberative and implemented mind sets during these states; they also hat to answer a general question about mood influences on task performance. Both quantitative and qualitative measures are used in these studies. The findings support the above general notions, and they additionally show that in the respondents' opinions negative mood effects are more variable than positive mood effects; further, that there are quite a few individual differences in assumed mood effects on task-related motivation.

Achievement↗

PubMed1992

Quantification of motor deficit in Parkinson's disease with a motor performance test series.

It was the purpose of the present study to quantify the expected motor deficit in parkinsonian patients with the computer assisted Motor Performance Test Series (MPS), version 05.87 by Schuhfried (1987) and to examine which of the motor test variables found correlate at a significance level of p less than 0.01 with items of "motor examination" recorded at neurological examination and "activities of daily living" of the Unified Parkinson's Disease Rating Scale (UPDRS), version 3.0. 38 patients with idiopathic Parkinson's disease (PD) stages I-IV according to Hoehn and Yahr, aged 41 to 73 years were studied. The study design, i.e. initial rating by the physician followed immediately by testing of motor function with MPS was strictly adhered to in each patient. Physician's rating of rigor and the scores of the semiquantitative tests (finger taps, hand movements and alternating movements) as expression of hypokinesia and the "activities of daily living" correlated with the 3 factors of the Motor Performance Test Series at a highly significant level independent of disease stage. Tremor is only partly and never significantly reflected in the motor data measured. Stages I-II and II-IV (Hoehn and Yahr) differ significantly in the representative data of the Motor Performance Test Series. The results of the study support the assumption that MPS is a valid instrument for quantitative measurement of the motor deficit in parkinsonian patients, but that only some subtests are "pathognomonic".

Activities of Daily Living↗

PubMed1992

An empirical evaluation of the Global Deterioration Scale for staging Alzheimer's disease.

OBJECTIVE: Although the Global Deterioration Scale has been widely used since its publication in 1982, its stages are based on implicit assumptions about the linearity, temporality, and interdependence of cognitive, functional, and behavioral impairment in Alzheimer's disease. The authors evaluated the validity of these assumptions and tested the hypothesis that psychopathology and functional impairment would occur in earlier stages than the Global Deterioration Scale predicts. METHOD: The analyses were based on data on 324 patients with Alzheimer's disease who were selected from a registry of such patients. Data analyses included 1) descriptive statistics on the frequency of psychiatric symptoms and difficulties with activities of daily living and 2) logistic regression, with symptoms and functional impairment as independent variables, to test for significant changes in patients' status between stages of the Global Deterioration Scale. RESULTS: More than 50% of the patients at stage 2 displayed psychopathology, and 32% had two or more symptoms. The significant increase in psychiatric symptoms occurred between stages 3 and 4, not between stages 5 and 6 as predicted by the Global Deterioration Scale. Impairment in functional status was observed at all stages, and significant increases occurred between stages 3 and 4 as well as between stages 5 and 6. CONCLUSIONS: Psychiatric symptoms and functional impairment occur earlier than predicted by the Global Deterioration Scale, and the rate of change is also different from that specified in the scale. Separate scales to describe cognitive, clinical, and functional status may be the best way to describe the illness until better multidimensional instruments are developed.

Activities of Daily Living↗