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Results for “posterior odds of causality”

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PubMed2024

BICEP: Bayesian inference for rare genomic variant causality evaluation in pedigrees.

Next-generation sequencing is widely applied to the investigation of pedigree data for gene discovery. However, identifying plausible disease-causing variants within a robust statistical framework is challenging. Here, we introduce BICEP: a Bayesian inference tool for rare variant causality evaluation in pedigree-based cohorts. BICEP calculates the posterior odds that a genomic variant is causal for a phenotype based on the variant cosegregation as well as a priori evidence such as deleteriousness and functional consequence. BICEP can correctly identify causal variants for phenotypes with both Mendelian and complex genetic architectures, outperforming existing methodologies. Additionally, BICEP can correctly down-weight common variants that are unlikely to be involved in phenotypic liability in the context of a pedigree, even if they have reasonable cosegregation patterns. The output metrics from BICEP allow for the quantitative comparison of variant causality within and across pedigrees, which is not possible with existing approaches.

Pedigree↗

PubMedDate not supplied

Case-control studies and Bayesian inference.

We outline the methods of Bayesian inference for applications to case-control studies. These methods appear as the natural way of making inferences, since much of the controversy that surrounds a specific case-control study is subjective. We derive conjugate prior distributions of exposure, posterior distributions of the ratio of the odds of being incident with a disease both with and without exposure to a potential causal agent, and convenient approximations. In particular, we show how one may carry out 'case-control studies' without necessarily having a control group. We illustrate these ideas with the data that first showed the relationship between in utero exposure to diethylstilbestrol and cancer of the vagina in young girls.

Adenocarcinoma↗

PubMed1999

Inhaled corticosteroids and cataract: prevalence, prevention and management.

Oral and topical (ocular) corticosteroids are known to have the potential to cause cataracts, but inhaled corticosteroids have generally been considered to be free of this adverse effect. However, a large epidemiological study has recently found a strong association in adults between use of inhaled corticosteroids and risk of posterior subcapsular cataract, the most serious type of cataract. This is likely to be a causal association as the association was strong (odds ratio of 10 for heavy users of corticosteroids compared with nonusers); in addition, there was a dose-response relationship and the association is biologically plausible. For people with asthma, the benefits of inhaled corticosteroids for management of their respiratory symptoms will be much greater than the risk of cataract. This is particularly true for children, in whom the risk of cataract is extremely low. Nevertheless, the existence of serious adverse effects of inhaled corticosteroids means they should be used for the shortest duration, and in the lowest dose, compatible with effective asthma management.

Administration, Inhalation↗

PubMed2004

Are ATM mutations 7271T-->G and IVS10-6T-->G really high-risk breast cancer-susceptibility alleles?

Two mutations of the ATM gene were recently suggested to confer breast cancer risks similar to mutations of BRCA1 or BRCA2. Here, we set out to confirm these findings in 961 families with non-BRCA1/BRCA2 breast cancer from diverse geographical regions. We did not detect the ATM 7271T-->G mutation in any family. The ATM IVS10-6T-->G mutation was detected in eight families, which was similar to its frequency among population-matched control individuals (pooled Mantel-Haenszel odds ratio = 1.60; 95% confidence interval = 0.48 to 5.35; P = 0.44). Bayesian analysis of linkage in the ATM IVS10-6T-->G-positive families showed an overall posterior probability of causality for this mutation of 0.008. We conclude that the ATM IVS10-6T-->G mutation does not confer a significantly elevated breast cancer risk and that ATM 7271T-->G is a rare event in familial breast cancer.

Alleles↗

PubMed2006

Imputation of individual cancer cases to occupational causes.

OBJECTIVES: Many potential occupational causes of cancer have been documented. Imputation of an individual cancer to occupational or other causes is, however, difficult. A method based on the Bayes theorem is proposed for assessing causal relationships at the individual level. METHODS: Causality assessment, dealing with four types of persons defined by exposure and the occurrence of cancer, was linked with imputation, only dealing with persons who have cancer and were exposed. Imputation was then formulated using the Bayes theorem, relating epidemiologic information regarding causes, a patient's exposure history, and the posterior odds that the cancer was caused by a suspected occupational exposure. Data needed to apply a Bayesian method were defined in terms of relative risks, proportion of people exposed in populations, and the frequency of a positive relevant characteristic for persons without cancer. A relevant characteristic was defined using a formal consensus between experts. The method was then illustrated with cases of mesothelioma and lung cancer in possible relation to asbestos. RESULTS: Experts defined the relevant characteristics as being qualification of occupational exposure, intensity of exposure, latency, disease characteristics, and presence of causal agent in the body. Application to mesothelioma and lung cancer cases illustrated the potential usefulness of the method. CONCLUSIONS: The importance of occupational exposure in the formulation of imputation underscores the need for available and reliable data sources on occupational exposures. The proposed method could become a powerful tool for the expert assessment of causes of cancer cases, provided data become available in individual files and the literature.

Aged↗

PubMed2002

Thrombotic thrombocytopenic purpura associated with clopidogrel: further evaluation.

BACKGROUND: Eleven cases of thrombotic thrombocytopenic purpura (TTP) associated with clopidogrel therapy have been published. OBJECTIVES: To perform a comprehensive causality assessment of the 11 published cases of TTP to assess quantitatively the extent to which clopidogrel was the causative factor. METHODS: The 11 reports of TTP were analyzed using the Bayesian Adverse Reaction Diagnostic Instrument to calculate the posterior probability (PsP) that clopidogrel caused the TTP based on epidemiological and clinical trials data (expressed as prior odds) and the clinical characteristics of each case (expressed as likelihood ratios). RESULTS: Clopidogrel was implicated as the causative factor of the TTP (PsP>0.75) in only five of the 11 cases. The PsP for clopidogrel was lowered by concomitant use of a statin, a history of cancer and the occurrence of relapsing TTP (in the absence of clopidogrel) in the remaining six cases. CONCLUSIONS: This systematic analysis provides strong evidence, based on the case information reported, that clopidogrel was the causative factor in at least some cases of TTP.

Bayes Theorem↗

PubMed2026

Bayesian Mendelian randomization reveals a protective effect of later age at first sexual intercourse against erectile dysfunction.

Erectile dysfunction (ED) is a prevalent health condition with significant psychosocial impacts, yet the causal role of age at first sexual intercourse (AFS) remains unclear. This study investigated the causal effect of AFS on the risk of ED using Mendelian randomization (MR) and Bayesian methods. Five traditional 2-sample MR analyses and 5 Bayesian MR analyses were performed using genome-wide association studies summary statistics from European populations. Sensitivity analyses included MR Egger regression, MR-pleiotropy residual sum and outlier, and Cochran Q-test. In mixed-sex cohorts (Groups 1 and 2), inverse variance weighted results demonstrated significant protective effects: odds ratio (OR) = 0.626, θ = -0.469, P = 2.73 × 10-6 for Group 1 and OR = 0.617, θ = -0.483, P = 3.56 × 10-5 for Group 2. The analyses for male-specific cohorts (Groups 3-10) showed weaker but consistent effects. For Group 3, OR = 0.643, θ = -0.442, P = .010. For Group 4, some instrumental variables associated with confounders were removed. The result became statistically insignificant: OR = 0.680, θ = -0.385, P = .064. For Group 5, the instrument selection criteria were relaxed and significance was retained: OR = 0.695, θ = -0.364, P = .016. For Groups 6 to 10, Bayesian MR was used to strengthen the inferences. In particular, for Group 8, which has a strongly informed prior, a posterior mean θ = -0.358 and a 95% credible interval (-0.575, -0.136) were obtained. This study provides evidence supporting a causal protective effect of later AFS on ED risk. While traditional MR analyses in male-specific cohorts yielded suggestive results, Bayesian MR analyses, which allow for the integration of prior evidence, provided more precise estimates and strengthened the causal inference. These findings may inform future sexual health policies. Strengths include the use of male-specific cohorts and Bayesian enhancement for weak instruments. Limitations include reliance on European-ancestry data and inability to stratify ED subtypes.

Male↗

PubMed2000

Hematologic dyscrasia associated with ticlopidine therapy: evidence for causality.

BACKGROUND: Several rare, potentially fatal types of hematologic dyscrasia, such as agranulocytosis, aplastic anemia, neutropenia, pancytopenia, thrombocytopenia and thrombotic thrombocytopenic purpura (TTP), have been associated with ticlopidine therapy. The extent to which ticlopidine is the causative factor has not been addressed quantitatively. METHODS: We identified 211 published case reports of hematologic dyscrasia associated with ticlopidine therapy from a MEDLINE search. We analyzed the 91 reports that could be evaluated, using the Bayesian Adverse Reaction Diagnostic Instrument to calculate the posterior probability that ticlopidine caused the hematologic dyscrasia based on epidemiologic and clinical trial data (prior odds) and case information (likelihood ratio). RESULTS: The median posterior probability values (and range) for agranulocytosis, aplastic anemia, neutropenia, pancytopenia, thrombocytopenia and TTP were 0.95 (0.53-0.98), 0.81 (0.57-0.93), 0.86 (0.75-0.96), 0.78 (0.61-0.89), 0.74 (0-0.92) and 1.0 (0.33-1.00) respectively. The posterior probability was 0.75 or greater in 82 (90%) of the case reports. INTERPRETATION: This systematic analysis provides stronger evidence to implicate ticlopidine as the causative factor in the various types of hematologic dyscrasia in most published case reports.

Bayes Theorem↗

PubMed2025

Circulating inflammatory proteins and osteomyelitis: A bidirectional Mendelian randomization and colocalization analysis.

Circulating inflammatory proteins (CIPs) have been implicated in the progression of osteomyelitis (OM); however, whether these proteins play a causal role or are merely a consequence remains unclear. This study aimed to assess the causal relationships between CIPs and OM using a bidirectional 2-sample Mendelian randomization (MR) approach. MR analyses were performed using genome-wide association study summary statistics for 91 inflammation-related proteins (n = 14,824) and OM (1881 cases and 3,91,037 controls). The inverse variance weighted method was used as the primary analytical approach, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to evaluate heterogeneity, horizontal pleiotropy, and robustness. Colocalization analysis was applied to identify shared causal variants, and pathway enrichment analysis was used to explore underlying biological mechanisms. Forward MR analysis revealed that elevated levels of tumor necrosis factor-beta (TNF-β) were significantly associated with increased OM risk (odds ratio [OR] = 1.132; 95% confidence interval [CI]: 1.052-1.217; false discovery rate [FDR] = 0.027). Conversely, decreased levels of osteoprotegerin (OR = 0.772; 95% CI: 0.671-0.889; FDR = 0.015) and adenosine deaminase (OR = 0.811; 95% CI: 0.736-0.894; FDR < 0.001) were associated with increased OM risk. Reverse MR analysis identified increased levels of interleukin-15 receptor alpha, C-X-C motif chemokine ligand 1, fms-related tyrosine kinase 3 ligand, interleukin-20, interleukin-10 (IL10), C-C motif chemokine ligand 19, and CXCL6 as being significantly associated with OM susceptibility (all FDR < 0.05). Colocalization analysis provided strong evidence for a shared causal variant between TNF-β and OM (posterior probability for hypothesis 4 = 0.999). Enrichment analyses indicated involvement of implicated proteins in Toll-like receptor signaling and T-helper 17 cell differentiation pathways. This study identified several CIPs - including TNF-β, osteoprotegerin, and adenosine deaminase - as potentially causal in OM development. These findings highlight promising targets for future immunomodulatory therapies aimed at preventing or mitigating osteomyelitis.

Humans↗