Association Test Research Articles

Identification of the Molecular Components of Enhancer-Mediated Gene Expression Variation in Multiple Tissues Regulating Blood Pressure.

Inter-individual variation in blood pressure (BP) arises in part from sequence variants within enhancers modulating the expression of causal genes. We propose that these genes, active in tissues relevant to BP physiology, can be identified from tissue-level epigenomic data and genotypes of BP-phenotyped individuals. We used chromatin accessibility data from the heart, adrenal, kidney, and artery to identify cis-regulatory elements (CREs) in these tissues and estimate the impact of common human single-nucleotide variants within these CREs on gene expression, using machine learning methods. To identify causal genes, we performed a gene-wise association test. We conducted analyses in 2 separate large-scale cohorts: 77 822 individuals from the Genetic Epidemiology Research on Adult Health and Aging and 315 270 individuals from the UK Biobank. We identified 309, 259, 331, and 367 genes (false discovery rate <0.05) for diastolic BP and 191, 184, 204, and 204 genes for systolic BP in the artery, kidney, heart, and adrenal, respectively, in Genetic Epidemiology Research on Adult Health and Aging; 50% to 70% of these genes were replicated in the UK Biobank, significantly higher than the 12% to 15% expected by chance (P<0.0001). These results enabled tissue expression prediction of these 988 to 2875 putative BP genes in individuals of both cohorts to construct an expression polygenic score. This score explained ≈27% of the reported single-nucleotide variant heritability, substantially higher than expected from prior studies. Our work demonstrates the power of tissue-restricted comprehensive CRE analysis, followed by CRE-based expression prediction, for understanding BP regulation in relevant tissues and provides dual-modality supporting evidence, CRE and expression, for the causality genes.

Climate-Related Financial Risk: Insights from a Semisystematic Review of the Literature and Implications for Financial Reporting

Synopsis The research problem This paper provides a semisystematic review of the literature on climate-related financial risk, with particular emphasis on whether that risk is adequately priced by financial markets and the implications of that risk assessment for financial reporting. Motivation This paper was motivated by a strong perception that financial markets have become increasingly exposed to the perils of climate change, and a concern for whether the rapid expansion of the literature on this topic sufficiently addresses financial markets’ correct pricing of the uncertainties inherent in these perils. Our particular goals were to understand the expansion of this literature, identify the originating and influential works that may have spurred this expansion, and provide new directions for research. The research question Our paper reviews the research on whether climate-related financial risk is adequately priced by the financial markets. Target population We examined a comprehensive sample of articles on climate-related financial risk published in the Financial Times’ Top 50 (FT50) accounting, finance, management, and business ethics journals over three decades, ending in 2022. Our analysis of the evolution of knowledge on climate-related financial risk also includes studies in non-FT50 journals (prior works) that may have spurred subsequent work in FT50 journals; non-FT50 journals (derivative works) that are inspired by the studies in FT50 journals; and set of studies that are similar to those in FT50 journals in terms of the topic (similar works) published in an array of non-FT50 journals. Adopted methodology We conducted a semisystematic review of knowledge flow based on bibliographic coupling, cocitation, and direct citation. Analyses We reviewed FT50 articles to examine the topics, methods, samples, and results. We compared FT50 articles with non-FT50 articles to explore their respective number of publications and average citations over time. We also examined the extent to which the FT50 and non-FT50 journals included accounting papers and the extent to which the top 20 papers, based on their impact (defined as the number of times a paper was considered an influential work by the FT50 journal papers), included accounting papers. Findings Compared to non-FT50 journals, we find that FT50 journals largely ignored climate-related financial risk until about 2010, and that the average citation of an FT50 publication was lower than a non-FT50 publication until around 2017. The fraction of FT50 and non-FT50 accounting journals publishing on climate-related financial risk remained low across all years. Moreover, the top 20 studies, based on their impact, included very few accounting papers. Our review of the content of the FT50 studies identifies traits of the literature that limit its generalizability, namely, a heavy emphasis on samples of U.S. corporations and the extensive use of association tests to develop the findings. Our review of the literature on the pricing effects of climate-related financial risk suggests that financial markets only partially price this risk and that fundamental questions relevant to policy remain unanswered.

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

BackgroundInflammatory bowel disease (IBD) and Parkinson’s disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity.MethodsWe analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD.ResultsThe analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein–protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD.ConclusionsOur study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.

Anticholinergic burden and the cognitive functions in elderly and senile patients with arterial hypertension

The aim of the study was to evaluate the effect of anticholinergic load (AHN) on cognitive functions (CF) in elderly and senile multimorbid patients with arterial hypertension (AH).Materials and methods. 330 patients aged 60 years and older with essential AH were included in the study (median age 79 [72; 84] years, 158 (51 %) of women). All the patients were underwent the assesment of CF using the Montreal Cognitive Assessment Scale (MoCA), Mini-Mental Status Scale (MMS), Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog), Trial Making Test (TMT), Digit Symbol Substitution Test (DSST), Verbal Association Test (literal (letter) and categorical (animal) associations), Boston Naming Test (BNT), Word-Color Interference Test, Stroop colorword conflict test. The anticholinergic load was determined using the anticholinergic load scale (Anticholinergic Cognitive Burden Scale, ACB).Results. Compared with patients who do not take anticholinergic drugs, multimorbid elderly and senile hypertensive patients with 2 or more points on the ACB scale had significantly lower final scores on the MoCA test (23 [21; 24.3] versus 24 [22; 25] points, respectively, p=0.042) and on MMSE (26 [24; 29] vs. 27.5 [25; 29] points, respectively, p=0.015), they spent statistically more time completing part B of the TMT test (217.5 [187.3; 246.3] vs. 204 [166.8; 247.3] seconds, respectively, p=0.038). The difference between the execution time of part B and part A of the TMT test in patients with 2 or more points on the ACB scale was statistically significantly greater than in patients with 0 points on this scale (141 [103.8; 168.5] versus 124 [83.8; 162] sec, respectively, p=0.034). Age, gender, education, and the structure of concomitant diseases did not differ between the groups.Conclusion. The results obtained indicate the adverse effect of аnticholinergic вurden on CF of multimorbid elderly and senile hypertensive patients and dictate the need to optimize pharmacotherapy in this category of patients.

The influence of depression and anxiety on cognition in people with multiple sclerosis: a cross-sectional analysis.

There are conflicting findings about the relationships between depression, anxiety, and cognitive dysfunction in people with multiple sclerosis (MS), and a paucity of research has examined the cumulative influence on cognition of depression plus anxiety. This study aimed to determine whether elevated symptoms of depression and anxiety alone or in combination are associated with worse cognition in people with MS. In this cross-sectional analysis, people with MS consecutively seen at a tertiary neuropsychiatry clinic completed the Hospital Anxiety and Depression Scale for symptoms of depression (HADS-D) and anxiety (HADS-A), and the Minimal Assessment of Cognitive Function in MS for cognitive indices. Accounting for covariates, regression models predicted cognitive indices from scores for HADS-D, HADS-A, and the interaction. Of 831 people with MS, 72% were female, mean age was 43.2years, and median Expanded Disability Status Scale score was 2.0. Depressive symptoms were independently predictive of lower verbal fluency (Controlled Oral Word Association Test, p < 0.01), verbal learning (California Verbal Learning Test-II (CVLT-II) total learning, p = 0.02), verbal delayed recall (CVLT-II delayed recall, p < 0.01), and processing speed (Symbol Digit Modalities Test, p < 0.01; three-second Paced Auditory Serial Addition Test (PASAT), p = 0.05; two-second PASAT, p = 0.01). Anxiety in people with depression predicted decreased visuospatial function (Judgment of Line Orientation, p = 0.05), verbal learning (p < 0.01), verbal delayed recall (p < 0.01), visuospatial recall (Brief Visuospatial Memory Test-Revised, p = 0.02), and executive function (Delis-Kaplan Executive Function System, p < 0.01). Anxiety alone was not independently predictive of cognition. In conclusion, depression, especially with comorbid anxiety, is associated with cognitive dysfunction in people with MS.

Low Anterior Resection Syndrome and Quality of Life of Patients After Sphincter Preservation Surgery: A Prospective Study.

Background After anterior resection (AR), one of the most debilitating complications is low anterior resection syndrome (LARS) seenin about 64% of patients. The severity of the LARS score wassignificantly correlated with neoadjuvant treatment, the extent of rectal surgery, complication by the anastomotic leak, female gender, and age < 64 years. In this study, weanalyzed the impact of various clinical factors on LARS and also the various domains of quality of life (QoL). Purpose To assess the incidence of LARS in patients undergoing sphincter-sparing surgery for rectal cancer after the patient starts long-term defecating per anus, change in the QoL, and relation to LARS and factors affecting it. Methods One year before, 72 patients who had undergone AR in the Regional Cancer Centre were interviewed by a trained interviewer and data was collected from the file. Thequestionnairesused were the Wexner Incontinence score, LARS Malayalam Questionnaire, and European Organisation For Research and Treatment of Cancer (EORTC) QLQ C30 Malayalam translations. Statistical measures The LARS score wasused to categorize patients into three grades. The scores werecompared with clinical and social factors using the χ2 test for association. Continuous variables were compared by the Spearman Rho test. Results Details of patients were studied(male: 55.6% (40) andfemale: 44.4% (32)). Fifty patientsunderwent low anterior resection (LAR). The mean LARSscore was 25.61, with 47.2% of patients having severe LARS score. The mean Wexner score was 6.84. The relation withtype of surgery, approach (laparoscopic vs open), or type of neoadjuvant therapy was not found to be significant. A higher LARS score did not impact overall QoL as assessed by FACT-C. Insomnia and diarrhea symptoms scores were significantly worsened. The pain score was worse for those undergoing stapler anastomosis. Wexner's score was worse for those who had received adjuvant chemotherapy. Role functioning score was better for AR compared to low anterior resection (LAR). Only distance from the anal verge was found to be a significant cause of LARS and was negatively correlated. Discussion LARS of severe degrees were seen in most patients. No modifiable risk factors were significantly found to affect the chance of LARS. However, LARS did not have a significant impact on QoL, neither did the type of surgery. So sphincter preservation can be offered to the patients, but all patients undergoing LAR should be counseled well about the risk ofLARS before surgery.

Association Analysis of Essential Tremor-Associated Genetic Variants in Sporadic Late-Onset Parkinson's Disease.

Parkinson's disease (PD) and Essential tremor (ET) are the two most common tremor diseases with recognized genetic pathogenesis. The overlapping clinical features suggest they may share genetic predispositions. Our previous study systematically investigated the association between rare coding variants in ET-associated genes and early-onset PD (EOPD), and found the suggestive association between teneurin transmembrane protein 4 (TENM4) and EOPD. In the current research, we explored the potential genetic interplay between ET-associated genetic loci/genes and sporadic late-onset PD (LOPD). We performed whole-genome sequencing in the 1962 sporadic LOPD cases and 1279 controls from mainland China. We first used logistic regression analysis to test the top 16 SNPs identified by the ET genome-wide association study for the association between ET and LOPD. Then we applied the optimized sequence kernel association testing to explore the rare variant burden of 33 ET-associated genes in this cohort. We did not observe a significant association between the included SNPs with LOPD. We also did not discover a significant burden of rare deleterious variants of ET-associated genes in association with LOPD risk. Our results do not support the role of ET-associated genetic loci and variants in LOPD. 1962 cases and 1279 controls were recruited to study the potential genetic interplay between ET-associated genetic loci/variants and sporadic LOPD.No significant association between the ET-associated SNPs and LOPD were observed.No significant burden of rare deleterious variants of ET-associated gene in LOPD risk were found.

A novel method for multiple phenotype association studies based on genotype and phenotype network.

Joint analysis of multiple correlated phenotypes for genome-wide association studies (GWAS) can identify and interpret pleiotropic loci which are essential to understand pleiotropy in diseases and complex traits. Meanwhile, constructing a network based on associations between phenotypes and genotypes provides a new insight to analyze multiple phenotypes, which can explore whether phenotypes and genotypes might be related to each other at a higher level of cellular and organismal organization. In this paper, we first develop a bipartite signed network by linking phenotypes and genotypes into a Genotype and Phenotype Network (GPN). The GPN can be constructed by a mixture of quantitative and qualitative phenotypes and is applicable to binary phenotypes with extremely unbalanced case-control ratios in large-scale biobank datasets. We then apply a powerful community detection method to partition phenotypes into disjoint network modules based on GPN. Finally, we jointly test the association between multiple phenotypes in a network module and a single nucleotide polymorphism (SNP). Simulations and analyses of 72 complex traits in the UK Biobank show that multiple phenotype association tests based on network modules detected by GPN are much more powerful than those without considering network modules. The newly proposed GPN provides a new insight to investigate the genetic architecture among different types of phenotypes. Multiple phenotypes association studies based on GPN are improved by incorporating the genetic information into the phenotype clustering. Notably, it might broaden the understanding of genetic architecture that exists between diagnoses, genes, and pleiotropy.

Exploring clinical specialists’ perspectives on the future role of AI: evaluating replacement perceptions, benefits, and drawbacks

Background of studyOver the past few decades, the utilization of Artificial Intelligence (AI) has surged in popularity, and its application in the medical field is witnessing a global increase. Nevertheless, the implementation of AI-based healthcare solutions has been slow in developing nations like Pakistan. This unique study aims to assess the opinion of clinical specialists on the future replacement of AI, its associated benefits, and its drawbacks in form southern region of Pakistan.Material and methodsA cross-sectional selective study was conducted from 140 clinical specialists (Surgery = 24, Pathology = 31, Radiology = 35, Gynecology = 35, Pediatric = 17) from the neglected southern Punjab region of Pakistan. The study was analyzed using χ2 - the test of association and the nexus between different factors was examined by multinomial logistic regression.ResultsOut of 140 respondents, 34 (24.3%) believed hospitals were ready for AI, while 81 (57.9%) disagreed. Additionally, 42(30.0%) were concerned about privacy violations, and 70(50%) feared AI could lead to unemployment. Specialists with less than 6 years of experience are more likely to embrace AI (p = 0.0327, OR = 3.184, 95% C.I; 0.262, 3.556) and those who firmly believe that AI knowledge will not replace their future tasks exhibit a lower likelihood of accepting AI (p = 0.015, OR = 0.235, 95% C.I: (0.073, 0.758). Clinical specialists who perceive AI as a technology that encompasses both drawbacks and benefits demonstrated a higher likelihood of accepting its adoption (p = 0.084, OR = 2.969, 95% C.I; 0.865, 5.187).ConclusionClinical specialists have embraced AI as the future of the medical field while acknowledging concerns about privacy and unemployment.

Association of obesity to reaction time and visual memory in schizophrenia

BackgroundBoth overweight and cognitive deficits are common among people with schizophrenia (SZ) and schizoaffective disorder. The results in earlier studies have been inconsistent on whether overweight is associated with cognitive deficits in psychotic disorders. AimsOur aim in this study was to detect possible associations between obesity and cognitive deficits among study participants with SZ and schizoaffective disorder. MethodsThe study sample included 5382 participants with a clinical diagnosis of SZ or schizoaffective disorder selected from the Finnish SUPER study. Obesity was measured both with body-mass index and waist circumference. The cognitive performance was evaluated with two tests from the Cambridge automated neuropsychological test battery: Reaction time was evaluated with the 5-choice serial reaction time task. Visual memory was evaluated with the paired associative learning test. The final analysis included a total sample of 4498 participants applicable for the analysis of the reaction time and 3967 participants for the analysis of the visual memory. ResultsObesity measured with body-mass index was associated with better performance in reaction time task among both female and male participants. Among male participants, overweight was associated with better performance in the visual memory test. The waist circumference was not associated with cognitive measures. ConclusionsThe results suggest that obesity in people with SZ or schizoaffective disorder might not be associated with cognitive deficits but instead with better cognitive performance. The results were opposite from earlier literature on the general population. More research is required to better understand whether the results might be partly caused by the differences in the etiology of obesity between the general population and people with SZ.

Assessing Implicit Theories in Sexual Offending Using Indirect Measures: Feasibility, Reliability, and Incremental Validity.

This study assessed psychometric qualities of indirect measures assessing Implicit Theories (ITs) of sexual offending: Implicit Association Task (IAT), Implicit Relational Assessment Procedure (IRAP), and Relational Responding Task (RRT). For comparison reasons, aggressive behavior was also assessed. In a male sample from the general population (N = 109), we assessed each measure's (a) feasibility (mean latency, error rate, passing criteria), (b) internal consistency, (c) convergent and discriminant validity, and (d) incremental and predictive validity. Results indicated that no indirect measure met all criteria. Although the IAT was reasonably feasible and reliable in measuring aggression, ITs could not be reliably assessed. The RRT was feasible and somewhat reliable in assessing ITs, whereas the IRAP showed limited feasibility, high task complexity, low reliability, and the presence of a method factor. No measure had incremental predictive validity over the use of self-report measures, although we note that the power to detect such associations was limited. As none of the indirect measures performed satisfactorily on the measured criteria, the use of these measures in clinical practice seems currently unwarranted to assess ITs.

Genetic polymorphisms associated with adverse pregnancy outcomes in nulliparas

Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA. In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1, respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20, GUCY1A2, and RPL7P20, respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well.

Data-Adaptive Multivariate Test for Genomic Studies Using Fused Lasso

In genomic studies, univariate analysis is commonly used to discover susceptible variants. It applies univariate regression for each variant and tests the significance of the regression coefficient or slope parameter. This strategy, however, may miss signals that are jointly detectable with other variants. Multivariate analysis is another popular approach, which tests grouped variants with a predefined group, e.g., based on a gene, pathway, or physical location. However, the power will be diminished if the modeling assumption is not suited to the data. Therefore, data-adaptive testing that relies on fewer modeling assumptions is preferable. Possible approaches include a data-adaptive test proposed by Ueki (2021), which applies to various data-adaptive regression models using a generalization of Yanai’s generalized coefficient of determination. While several regression models are possible choices for the data-adaptive test, this paper focuses on the fused lasso that can count for the effect of adjacent variants and investigates its performance through comparison with other existing tests. Simulation studies demonstrate that the test using fused lasso has a high power compared to the existing tests including the univariate regression test, saturated regression test, SKAT (sequence kernel association test), burden test, SKAT-O (optimized sequence kernel association test), and the tests using lasso, ridge, and elastic net when assuming a similar effect of adjacent variants.

Association between vaginal microbiota and vaginal inflammatory immune markers in postmenopausal women.

In premenopausal individuals, vaginal microbiota diversity and lack of Lactobacillus dominance are associated with greater mucosal inflammation, which is linked to a higher risk of cervical dysplasia and infections. It is not known if the association between the vaginal microbiota and inflammation is present after menopause, when the vaginal microbiota is generally higher-diversity and fewer people have Lactobacillus dominance. This is a post hoc analysis of a subset of postmenopausal individuals enrolled in a randomized trial for treatment of moderate-severe vulvovaginal discomfort that compared vaginal moisturizer, estradiol, or placebo. Vaginal fluid samples from 0, 4, and 12 weeks were characterized using 16S rRNA gene sequencing (microbiota) and MesoScale Discovery (vaginal fluid immune markers: IL-1b, IL-1a, IL-2, IL-6, IL-18, IL-10, IL-9, IL-13, IL-8, IP10, MIP1a, MIP1b, MIP3a). Global associations between cytokines and microbiota (assessed by relative abundance of individual taxa and Shannon index for alpha, or community, diversity) were explored, adjusting for treatment arm, using linear mixed models, principal component analysis, and Generalized Linear Mixed Model + Microbiome Regression-based Kernel Association Test (GLMM-MiRKAT). A total of 119 individuals with mean age of 61 years were included. At baseline, 29.5% of participants had a Lactobacillus -dominant vaginal microbiota. Across all timepoints, alpha diversity (Shannon index, P = 0.003) was highly associated with immune markers. Individual markers that were associated with Lactobacillus dominance were similar to those observed in premenopausal people: IL-10, IL-1b, IL-6, IL-8 (false discovery rate [FDR] < 0.01), IL-13 (FDR = 0.02), and IL-2 (FDR = 0.09). Over 12 weeks, change in alpha diversity was associated with change in cytokine concentration (Shannon, P = 0.018), with decreased proinflammatory cytokine concentrations observed with decreasing alpha diversity. In this cohort of postmenopausal individuals, Lactobacillus dominance and lower alpha diversity were associated with lower concentrations of inflammatory immune markers, as has been reported in premenopausal people. This suggests that after menopause lactobacilli continue to have beneficial effects on vaginal immune homeostasis, despite lower prevalence.

Adolescents' implicit and explicit attitudes toward their peers with genetic conditions.

Previous research has demonstrated that children lacking knowledge about genetic disorders may have harmful attitudes toward people with disabilities, but disability awareness can successfully modify these attitudes. We explored adolescents' implicit and explicit attitudes towardpeers with genetic conditions to determine whether improved genetics/genomics literacy can mitigate the impact of ableism in this population. English-speaking adolescents (10-18 years) from British Columbia were invited to complete a Disability Attitudes Implicit Association Test (DA-IAT) and participate in a semi-structured focus group centering on a fictionalized vignette about an adolescent with Down syndrome. We used pragmatism as an analytical paradigm. Descriptive and inferential statistics were used to analyze DA-IAT and sociodemographic data; phronetic iterative analysis with constant comparison as a coding strategy for transcripts; and interpretive description to develop a conceptual model. Twenty-two adolescents completed the DA-IAT and participated in one of four focus groups. Participants had a statistically significant implicit preference for non-disabled people (D-score = 0.72, SD = 0.44; t = 7.18, p < .00001). They demonstrated greater diversity in their explicit attitudes during the focus groups. Although participants articulated a positive attitude towardimproved genetics education, results demonstrate their belief that social and personal interactions with disabled peers would be essential to address negative perceptions. This study lays important groundwork to understand, explain, and influence the negative attitudes of adolescents towardindividuals with disabilities. Findings will be used to inform the design of interventions that address biased perceptions of people with genetic disorders, with the goal of reducing prejudices and improving social interactions.

The Implicit Association Test and its difficulty(ies): Introducing the test difficulty concept to increase the true-score variance and, consequently, the predictive power of implicit association tests.

We introduce the test difficulty concept from classical test theory to tackle the issue of low predictive power of implicit association tests (IATs). Following classical test theory, we argue that IATs of moderate difficulty (defined as mean IAT scores of zero) have more predictive power than IATs of extreme difficulties (defined as mean IAT scores deviating strongly from zero). Furthermore, we assume this relationship to be mediated by the true-score variance in IAT scores, with moderate difficulty resulting in more true-score variance. To test our hypotheses, we used nonexperimental (Studies 1 and 2) and experimental designs (Study 3). In Studies 1 and 2, we compared IATs of different test difficulties with regard to their ability to predict direct attitude measures, drawing on the Attitudes, Identities, and Individual Differences study. In Study 1, a subset of 95 attitude IATs (n = 127,259) was analyzed using multilevel structural equation models. As expected, IAT test difficulty strongly moderated the predictive power of IATs, and this effect was mediated by IAT true-score variance. In Study 2, we replicated the results with the same analyses but a different subset of 95 identity IATs (n = 43,745). In Study 3, we experimentally manipulated the IAT test difficulty. In total, three IATs (n = 480) were analyzed using multigroup structural equation models. Again, the IAT closer to moderate difficulty had more true-score variance and predictive power than the IATs of extreme difficulty. Accordingly, for correlational research, we recommend developing moderately difficult IATs to maximize IAT true-score variance and provide suggestions on how to achieve that. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Emergency Department Triage Chief Complaints Among Children Evaluated for Physical Abuse Concerns.

The aims of this study were to describe chief complaints provided at emergency department triage for young children ultimately given a diagnosed with injuries concerning for physical abuse and compare chief complaints by hospital child protection team assessment (abuse most likely, accident most likely, undetermined) among children younger than 2 years who were the subject of a report to child protective services. This is a retrospective review of children evaluated by the child protection team at an urban children's hospital over a 5-year period. Children younger than 2 years who were the subject of a report to child protective services for suspected physical abuse were included. Chief complaints noted in emergency department triage notes were categorized as follows: 1, medical sign or symptom; 2, accidental trauma incident; 3, identified injury; 4, concern for abuse; or 5, multiple unrelated complaints. Child protection team assessments were categorized as follows: 1, abuse most likely; 2, accident most likely; or 3, undetermined. We used descriptive statistics and tests of association (χ 2 , Fisher exact, Kruskal-Wallis). Median age of the 422 children included was 4.9 months. Child protection team assessment was abuse most likely in 44%, accident most likely in 23%, and undetermined in 34%. Chief complaints in the overall sample were 39% medical, 29% trauma incident, 16% injury, 10% abuse concern, and 6% multiple unrelated. When the abuse most likely and accident most likely groups were compared, medical chief complaints were more common in the former (47% vs 19%, P < 0.001), whereas trauma incident chief complaints were more common in the latter (19% vs 64%, P < 0.001). Most common medical complaints in the abuse most likely group were altered mental status, abnormal limb use, swelling, pain, apnea, and vomiting. Many children found to have injuries concerning for abuse (47%) present without mention of trauma, injury, or abuse concern as part of the chief complaint. Our findings suggest important topics to include in training physicians about recognition of abuse.

Abstract PO2-19-01: A Single-Arm Prospective Study of the Neurocognitive Changes Occurring in Breast Cancer Patients on Aromatase Inhibitors. Is There a Difference Between Objective and Perceived Neurocognition?

Abstract Background: Estrogen (ER) and Progesterone (PR) receptors are rich in regions of the brain involved in cognitive functions, like the hippocampus and cerebral cortex. Animal models have shown that estradiol regulates neurocognition and plays an important role in the normal brain development. Hormone positive (HR+) breast cancers (BC) comprise 70% of the disease and the standard of care in the post-menopausal group is the use of Aromatase Inhibitors (AI) for at least 5 years. While “chemo brain” is a well-recognized term, neurocognitive changes from estrogen inhibition by AI have not been clearly defined. As neurocognition is multi-faceted, information on specific aspects affected by AI use is unclear. We hope to answer this through our trial. Design: The study is a single arm, self-controlled prospective observational cohort study in which, post-menopausal BC patients who are to be started on AIs will undergo a battery of neurocognitive tests just before starting AI, at 6 months and at 12 months after being on AI. The changes at 6 and 12 months will be compared to baseline. The tests will involve objective [Hopkins verbal learning test revised (HVLT), Controlled Oral Word Association Test from Multilingual Aphasia Examination, Trial Making Test A and B, and Recall and Recognition of Word List encoded from the HVLT] and subjective/patient-reported [The Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog)] components. Tests for anxiety [Generalized Anxiety Disorder (GAD)–7], depression [Patient Health Questionnaire (PHQ)-9] and working memory (Working Memory Tasks from the Wechsler Adult Intelligence Scale) will also be assessed. While the objective tests involve providing patients with specific instructions and asking them to complete the tasks, the FACT Cog questionnaire uses a self-reported 37-item questionnaire enabling assessment of their perceived symptoms. The tests have been summarized in the table. Eligibility criteria: ER/PR+ post-menopausal BC and DCIS patients who are English speaking and are planning to start AIs will be included. Patients who have received hormonal therapy or chemotherapy in the past, those who are scheduled to receive chemotherapy, those who have undergone Whole brain Radiation therapy (RT), those with a premenopausal status, and those having comorbid conditions that could affect cognitive functioning (like any form of dementia or brain metastasis) will be excluded. Specific aims: Our aim is to see if there are progressive neurocognitive changes compared to an age-appropriate baseline and to see if changes to both objective and perceived cognitive changes occur over the course of AI use, in post-menopausal HR+ BC patients. Statistical methods: The T-test and McNemer test will be used. The normal values provided from the test may be used as a standard to justify normal or abnormal values from the collected data. Therefore, a percentage of normal (or abnormal) subjects in each time point can be derived and compared using the McNemar's test. Present accrual and target accrual: 4 patients have been accrued as of June 2023 with a target accrual of 80 patients [80% power to detect a significant change, at a p of 0.05]. Contact information for people with a specific interest in the trial: Dr Abirami Sivapiragasam (abisiva2019@yahoo.com), Dr Sam Benjamin (benjamis@upstate.edu), Dr Prashanth Ashok Kumar (ashokkup@upstate.edu), Amy Bubb (bubbam@upstate.edu). Summary of the neurocognitive tests employed in the trial. Citation Format: Prashanth Ashok Kumar, Erinn McDowell, Amy Bubb, Danning Huang, Susan Sperry, Sam Benjamin, Abirami Sivapiragasam. A Single-Arm Prospective Study of the Neurocognitive Changes Occurring in Breast Cancer Patients on Aromatase Inhibitors. Is There a Difference Between Objective and Perceived Neurocognition? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-01.

Abstract PO5-09-03: Multi-tissue transcriptome-wide association studies identified genes for intrinsic subtypes of breast cancer

Abstract Background: Though several genome-wide association studies (GWAS) of breast cancer (BC) have identified common variants which differ between intrinsic subtypes, the genes through which these variants act through to impact BC risk have not been fully established. Furthermore, transcriptome-wide association studies (TWAS) have thus far been primarily employed to identify genes associated with overall BC risk, while overlooking how the influence of common variation on gene expression may contribute to subtype-specific differences. Methods: In this study, we performed two complementary multi-tissue TWASs for each of the following BC intrinsic subtypes: Luminal A-like, Luminal B-like, Luminal B/HER2-negative-like, HER2-enriched-like, Triple Negative BC. These two approaches included 1) an expression-based approach that collated TWAS signals from expression quantitative trait loci (eQTLs) across multiple tissues using the Aggregated Cauchy Association Test (ACAT) and 2) a splicing-based approach that utilized two applications of ACAT to collate splicing QTLs (sQTLs) for a given gene in a tissue and then across tissues. To perform these two TWASs, we utilized e/sQTL models trained in 11 tissues from the Genotype-Tissue Expression Project including breast, ovary, uterus, vagina, EBV-transformed lymphocytes, whole blood, spleen, liver, subcutaneous adipose, visceral adipose, and cell-cultured fibroblasts. GWAS summary statistics were previously generated from 133,384 BC cases and 113,789 controls who were participants in the Breast Cancer Association Consortium (BCAC). We further performed our TWAS while conditioning e/sQTL effect sizes on nearby GWAS index SNPs. Additionally, we utilized gene-based fine-mapping of eQTLs and sQTL to identify candidate causal genes for each intrinsic subtype. Results: Overall, we identified 164 genes in 69 loci that were associated with Luminal A-like, 19 genes in 9 loci with Luminal B-like, 18 genes in 11 loci with Luminal B/HER2-negative-like, 10 genes in 7 loci with HER2-enriched-like, and 29 genes in 12 loci with TNBC. Among these genes, 17 genes had not been reported in previous TWAS of BC, and 140 genes, 1 gene, 2 genes, 2 genes, and 16 genes were uniquely associated with each of the intrinsic subtypes, respectively. Additionally, we identified one gene associated with Luminal A-like and one gene with Luminal B-like BC that were each in a locus located at least 1.4 Mb from published GWAS hits. Furthermore, we identified 106, 11, 10, 5, and 21 candidate causal genes for each of the intrinsic subtypes, respectively, that had a posterior inclusion probability of 0.9 in at least one e/sQTL. Conclusion: In summary, our multi-tissue TWAS corroborated previous GWAS loci for overall BC risk and intrinsic subtypes, while underscoring how common variation impacts BC etiology by modulating the expression and splicing of genes in multiple tissue types. Citation Format: James Li, Julian McClellan, Haoyu Zhang, Guimin Gao, Dezheng Huo. Multi-tissue transcriptome-wide association studies identified genes for intrinsic subtypes of breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-09-03.

Clinical, behavioral, and electrophysiological profiles along a continuum of suicide risk: evidence from an implicit association task.

An urgent need exists to identify neural correlates associated with differing levels of suicide risk and develop novel, rapid-acting therapeutics to modulate activity within these neural networks. Electrophysiological correlates of suicide were evaluated using magnetoencephalography (MEG) in 75 adults with differing levels of suicide risk. During MEG scanning, participants completed a modified Life-Death Implicit Association Task. MEG data were source-localized in the gamma (30-58 Hz) frequency, a proxy measure of excitation-inhibition balance. Dynamic causal modeling was used to evaluate differences in connectivity estimates between risk groups. A proof-of-concept, open-label, pilot study of five high risk participants examined changes in gamma power after administration of ketamine (0.5 mg/kg), an NMDAR antagonist with rapid anti-suicide ideation effects. Implicit self-associations with death were stronger in the highest suicide risk group relative to all other groups, which did not differ from each other. Higher gamma power for self-death compared to self-life associations was found in the orbitofrontal cortex for the highest risk group and the insula and posterior cingulate cortex for the lowest risk group. Connectivity estimates between these regions differentiated the highest risk group from the full sample. Implicit associations with death were not affected by ketamine, but enhanced gamma power was found for self-death associations in the left insula post-ketamine compared to baseline. Differential implicit cognitive processing of life and death appears to be linked to suicide risk, highlighting the need for objective measures of suicidal states. Pharmacotherapies that modulate gamma activity, particularly in the insula, may help mitigate risk.Clinicaltrials.gov identifier: NCT02543983, NCT00397111.