Although childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or ...duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship.
Prospective data came from the Avon Longitudinal Study of Parents and Children (n = 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association.
Recency was the best fitting theoretical model for the effect of physical/sexual abuse (girls r2 = 2.35%; boys r2 = 1.68%). Both recency (girls r2 = 1.55%) and accumulation (boys r2 = 1.71%) were the best fitting models for caregiver physical/emotional abuse. Sensitive period models were chosen alone (parent legal problems in boys r2 = 0.29%) and with accumulation (financial stress in girls r2 = 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22-1.18).
Child psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity.
Neoantigen presentation arises as a result of tumor-specific mutations and is a critical component of immune surveillance that can be abrogated by somatic LOH of the human leukocyte antigen class I ...(HLA-I) locus. To understand the role of HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset of 83,644 patient samples, a small subset of which had treatment outcomes with immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was frequent at intermediate TMB, yet prevalence decreased above 30 mutations/megabase, suggesting highly mutated tumors require alternate immune evasion mechanisms. In ICI-treated patients with nonsquamous non-small cell lung cancer, HLA-I LOH was a significant negative predictor of overall survival. Survival prediction improved when combined with TMB, suggesting TMB with HLA-I LOH may better identify patients likely to benefit from ICIs. SIGNIFICANCE: This work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected "Goldilocks" relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH as a significant negative predictor of outcomes after ICI treatment. These data informed a combined predictor of outcomes after ICI and have implications for tumor vaccine development.
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Comparative effectiveness studies of cancer therapeutics in observational data face confounding by patterns of clinical treatment over time. The validity of survival analysis in longitudinal health ...records depends on study design choices including index date definition and model specification for covariate adjustment.
Overall survival in cancer is a multi-state transition process with mortality and treatment switching as competing risks. Parametric Weibull regression quantifies proportionality of hazards across lines of therapy in real-world cohorts of 12 solid tumor types. Study design assessments compare alternative analytic models in simulations with realistic disproportionality. The multi-state simulation framework is adaptable to alternative treatment effect profiles and exposure patterns.
Event-specific hazards of treatment-switching and death are not proportional across lines of therapy in 12 solid tumor types. Study designs that include all eligible lines of therapy per subject showed lower bias and variance than designs that select one line per subject. Confounding by line number was effectively mitigated across a range of simulation scenarios by Cox proportional hazards models with stratified baseline hazards and inverse probability of treatment weighting.
Quantitative study design assessment can inform the planning of observational research in clinical oncology by demonstrating the potential impact of model misspecification. Use of empirical parameter estimates in simulation designs adapts analytic recommendations to the clinical population of interest.
•Mortality and treatment switching survival times are competing risks in a multi-state model.•Hazards are not proportional across lines of therapy in real-world data.•We compare retrospective study designs for treatment effects and effect modifiers.•Allowing repeated observations per subject with robust std errors is recommended.
Increases in circulating LDL cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) concentrations are significant risk factors for cardiovascular disease (CVD). We assessed direct LDL-C ...and hsCRP concentrations compared to standard risk factors in the Framingham Offspring Study.
We used stored frozen plasma samples (-80 °C) obtained after an overnight fast from 3147 male and female participants (mean age, 58 years) free of CVD at cycle 6 of the Framingham Offspring Study. Overall, 677 participants (21.5%) had a CVD end point over a median of 16.0 years of follow-up. Total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C), direct LDL-C (Denka Seiken and Kyowa Medex methods), and hsCRP (Dade Behring method) concentrations were measured by automated analysis. LDL-C was also calculated by both the Friedewald and Martin methods.
Considering all CVD outcomes on univariate analysis, significant factors included standard risk factors (age, hypertension, HDL-C, hypertension treatment, sex, diabetes, smoking, and TC concentration) and nonstandard risk factors (non-HDL-C, direct LDL-C and calculated LDL-C, TG, and hsCRP concentrations). On multivariate analysis, only the Denka Seiken direct LDL-C and the Dade Behring hsCRP were still significant on Cox regression analysis and improved the net risk reclassification index, but with modest effects. Discordance analysis confirmed the benefit of the Denka Seiken direct LDL-C method for prospective hard CVD endpoints (new-onset myocardial infarction, stroke, and/or CVD death).
Our data indicate that the Denka Seiken direct LDL-C and Dade Behring hsCRP measurements add significant, but modest, information about CVD risk, compared to standard risk factors and/or calculated LDL-C.
Genome-wide association studies often collect multiple phenotypes for complex diseases. Multivariate joint analyses have higher power to detect genetic variants compared with the marginal analysis of ...each phenotype and are also able to identify loci with pleiotropic effects. We extend the unified score-based association test to incorporate family structure, apply different approaches to analyze multiple traits in GAW20 real samples, and compare the results. Through simulation studies, we confirm that the Type I error rate of the pedigree-based unified score association test is appropriately controlled. In marginalanalysis of triglyceride levels, we found 1 subgenome-wide significant variant on chromosome 6. Joint analyses identified several suggestive genome-wide significant signals, with the pedigree-based unified score association test yielding the greatest number of significant results.
Existing academic literature consistently points to a changing role for modern fathers in which they take an egalitarian role in the caregiving responsibilities for their children. Despite this, ...fathers are observed to continue to dominate the realms of full‐time working, aligning to more traditional breadwinning mentalities than such trends might suggest, raising questions around inequality. Fathers at work have previously been found to encounter challenges within the workplace when they alter, or consider altering their work patterns due to caregiving responsibilities. Employing a sample of working parents and managers, this paper explores how caregiving fathers are perceived within organizations and in considering their experiences, provides a nuanced and detailed understanding of the ways in which mistreatment for caregiving fathers manifests within contemporary UK workplaces. Caregiving fathers are found to face specific challenges termed “fatherhood forfeits” such as perceived idleness, suffering mockery, and being viewed with suspicion by male and female co‐workers. Actions are proposed to address “fatherhood forfeits” that include specific organizational training interventions and the importance of workplace role modeling.
Meta-analysis has been widely used in genetic association studies to increase sample size and to improve power, both in the context of single-variant analysis, as well as for gene-based tests. ...Meta-analysis approaches for haplotype analysis have not been extensively developed and used, and have not been compared with other ways of jointly analysing multiple genetic variants.
We propose a novel meta-analysis approach for a gene-based haplotype association test, and compare it with an existing meta-analysis approach of the sequence kernel association test (SKAT), using the unrelated samples and family samples of the Genetic Analysis Workshop 19 data sets. We performed association tests with diastolic blood pressure and restricted our analyses to all variants in exonic regions on all odd chromosomes.
Meta-analysis of haplotype results and SKAT identified different genes. The most significantly associated gene identified by SKAT was the
gene on chromosome 3 with a
value of 7.0 × 10
. Two of the most associated genes identified by the haplotype method were
(
= 6.7 × 10
) on chromosome 1 and
(
= 3.3 × 10
) on chromosome 5. Both genes were previously implicated in blood pressure regulation and hypertension.
We compared two meta-analysis approaches to jointly analyze multiple variants: SKAT and haplotype tests. The difference in observed results may be because the haplotype method considered all observed haplotypes, whereas SKAT weighted variants inversely to their minor allele frequency, masking the effects of common variants. The two approaches identified different top genes, and appear to be complementary.
The study of DNA methylation quantitative trait loci (meQTLs) helps dissect regulatory mechanisms underlying genetic associations of human diseases. In this study, we conducted the first genome-wide ...examination of genetic drivers of methylation variation in response to a triglyceride-lowering treatment with fenofibrate (response-meQTL) by using an efficient analytic approach.
Subjects (
= 429) from the GAW20 real data set with genotype and both pre- (visit 2) and post- (visit 4) fenofibrate treatment methylation measurements were included. Following the quality control steps of removing certain cytosine-phosphate-guanine (CpG) probes, the post-/premethylation changes (post/pre) were log transformed and the association was performed on 208,449 CpG sites. An additive linear mixed-effects model was used to test the association between each CpG probe and single nucleotide polymorphisms (SNPs) around ±1 Mb region, with age, sex, smoke, batch effect, and principal components included as covariates. Bonferroni correction was applied to define the significance threshold (
< 5.6 × 10
, given a total of 89,217,303 tests). Finally, we integrated our response-meQTL (re-meQTL) findings with the published genome-wide association study (GWAS) catalog of human diseases/traits.
We identified 1087 SNPs as
re-meQTLs associated with 610 CpG probes/sites located in 351 unique gene loci. Among these 1087
re-meQTL SNPs, 229 were unique and 6 were co-localized at 8 unique disease/trait loci reported in the GWAS catalog (enrichment
= 1.51 × 10
). Specifically, a lipid SNP, rs10903129, located in intron regions of gene
, was a re-meQTL (
= 3.12 × 10
) associated with the CpG probe cg09222892, which is in the upstream region of the gene
indicating a new target gene for rs10903129. In addition, we found that SNP rs12710728 has a suggestive association with cg17097782 (
= 1.77 × 10
), and that this SNP is in high linkage disequilibrium (LD) (R
> 0.8) with rs7443270, which was previously reported to be associated with fenofibrate response (
= 5.00 × 10
).
By using a novel analytic approach, we efficiently identified thousands of
re-meQTLs that provide a unique resource for further characterizing functional roles and gene targets of the SNPs that are most responsive to fenofibrate treatment. Our efficient analytic approach can be extended to large response quantitative trait locus studies with large sample sizes and multiple time points data.
The development of more remote sources of advice has been a notable feature of the contemporary human resource (HR) function. However, the consequences for the management of workplace conflict are ...largely ignored within the academic literature. This study draws on data from two qualitative studies, which examine the experiences of HR practitioners (HRPs), line managers and trade union representatives in handling and resolving conflict. It explores how different dimensions of organisational proximity shape the relationships between HRPs and other key stakeholders, and the impact of this on conflict management. The findings suggest that formal, risk averse approaches to conflict are not simply a result of geographical distance. Instead, functional specialisation has not only eroded cognitive and social proximity between HRPs, line managers and employee representatives but also within the HR function itself. This has triggered the reinforcement of bureaucratic control and embedded responses that emphasise compliance rather than resolution.
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