Benjamini-Hochberg Adjustment Research Articles

A machine learning approach for identification of gastrointestinal predictors for the risk of COVID-19 related hospitalization.

Background and aimCOVID-19 can be presented with various gastrointestinal symptoms. Shortly after the pandemic outbreak, several machine learning algorithms were implemented to assess new diagnostic and therapeutic methods for this disease. The aim of this study is to assess gastrointestinal and liver-related predictive factors for SARS-CoV-2 associated risk of hospitalization.MethodsData collection was based on a questionnaire from the COVID-19 outpatient test center and from the emergency department at the University Hospital in combination with the data from internal hospital information system and from a mobile application used for telemedicine follow-up of patients. For statistical analysis SARS-CoV-2 negative patients were considered as controls in three different SARS-CoV-2 positive patient groups (divided based on severity of the disease). The data were visualized and analyzed in R version 4.0.5. The Chi-squared or Fisher test was applied to test the null hypothesis of independence between the factors followed, where appropriate, by the multiple comparisons with the Benjamini Hochberg adjustment. The null hypothesis of the equality of the population medians of a continuous variable was tested by the Kruskal Wallis test, followed by the Dunn multiple comparisons test. In order to assess predictive power of the gastrointestinal parameters and other measured variables for predicting an outcome of the patient group the Random Forest machine learning algorithm was trained on the data. The predictive ability was quantified by the ROC curve, constructed from the Out-of-Bag data. Matthews correlation coefficient was used as a one-number summary of the quality of binary classification. The importance of the predictors was measured using the Variable Importance. A 2D representation of the data was obtained by means of Principal Component Analysis for mixed type of data. Findings with the p-value below 0.05 were considered statistically significant.ResultsA total of 710 patients were enrolled in the study. The presence of diarrhea and nausea was significantly higher in the emergency department group than in the COVID-19 outpatient test center. Among liver enzymes only aspartate transaminase (AST) has been significantly elevated in the hospitalized group compared to patients discharged home. Based on the Random Forest algorithm, AST has been identified as the most important predictor followed by age or diabetes mellitus. Diarrhea and bloating have also predictive importance, although much lower than AST.ConclusionSARS-CoV-2 positivity is connected with isolated AST elevation and the level is linked with the severity of the disease. Furthermore, using the machine learning Random Forest algorithm, we have identified the elevated AST as the most important predictor for COVID-19 related hospitalizations.

Workplace-related musculoskeletal injury trends in the United States from 1992 to 2018

IntroductionThe purpose of our study is to assess workplace-related musculoskeletal (wrMSK) injury trends by utilizing Bureau of Labor Statistics (BLS) data. We hypothesize that trunk injuries are the most commonly reported, injuries occur most frequently in the manufacturing sector, and that injury type occurrence differs according to body region affected. MethodsThis study assessed wrMSK injury data provided by the BLS from 1992 to 2018. The three main body regions analyzed were lower extremity (LE), upper extremity (UE), and trunk. Injury data was also assessed by industrial sector (Agriculture, Manufacturing, Healthcare, and Construction) and injury type (fractures, multiple injuries, sprains/strains/tears, tendonitis, cuts/lacerations, pain/soreness, and bruises). Negative binomial regression and pairwise comparisons with a Benjamini-Hochberg adjustment were utilized to compare calculated incidence rate ratios for wrMSK injuries. Exponentiated beta estimates were used to calculate the estimated annual percent changes of wrMSK injuries within each industrial sector. ResultsOccurrence of wrMSK injuries from 1992 to 2018 was significantly lower for LE when compared to both upper extremity and trunk (p < 0.001). Manufacturing is shown to be the industry with the most wrMSK injuries in each of UE, LE, and trunk. wrMSK injuries were shown to decrease in each industrial sector over the timespan assessed, with the greatest percent change occurring in the manufacturing sector. Lacerations and tendonitis were the most common diagnosis types in UE, while pain/soreness and strains/sprains/tears were most common in trunk and bruises were most common in LE. DiscussionFrom 1992 to 2018, trunk injuries were the most frequently occurring wrMSK injury, but not to a significantly higher degree than upper extremity injuries. wrMSK injury types that may require orthopedic surgical care affect specific body regions to different degrees, with cuts/lacerations and tendonitis most commonly affecting the upper extremity. Thus, it appears that wrMSK injuries in the upper extremity are of particular importance from an orthopedic care perspective.

Abstract PO-155: Racial heterogeneity in the molecular landscape of pancreatic adenocarcinoma: A call for action

Abstract Background: Pancreatic adenocarcinoma (PDAC) is an aggressive cancer predicted to be the second leading cause of cancer mortality in the next decade. Significant disparities in the incidence rate and outcomes of Black patients with PDAC have recently been reported. Efforts to characterize the molecular landscape of PDAC are ongoing; however, the molecular mechanisms driving cancer in PDAC patients remain largely unexplored with respect to sociocultural race. In this study, we utilized the Cancer Genome Atlas (TCGA) dataset to describe the somatic mutation, DNA methylation and gene expression profiles of PDAC patients with respect to sociocultural race in an effort to elucidate the racial heterogeneity in pancreatic carcinogenesis. Methods: This study involved accessing the public TCGA dataset for all patients with diagnosed PDACs. We filtered this cohort to include only patients with available racial information and matched DNA methylation, mRNA expression and simple somatic mutation data (n = 150). We analyzed the frequency and nature of non-silent simple somatic mutations for our cohort, both combined and separated by sociocultural race, and calculated the top differentially-methylated and differentially-expressed genes, using a maximum p-value of 0.01 for the Benjamini-Hochberg adjustment method as our cut-off. Results: We observed the four previously reported pancreatic adenocarcinoma driver genes (KRAS, TP53, SMAD4, and CDKN2A) to be the genes most frequently mutated in White (n = 132) and Asian (n = 9) PDAC samples. In Black (n = 5) samples, PDAC appears to be only partially driven by mutation of these driver genes. We found Black PDAC samples have a distinct mutational landscape and harbor somatic mutations in additional genes, including: CSMD2 (42.9%), RYR1 (28.6%), CBLL2 (28.6%), ANKRD24 (28.6%), SAMD7 (28.6%). The DNA methylation landscape of PDAC patients is also distinct with respect to sociocultural race, with the majority of differentially-methylated loci present to a greater degree in Black (53.8%) or Asian samples (28.2%), compared to White (17.9%) samples. Gene expression data also follow this trend, with the majority of genes showing the highest degree of differential expression in Black (82.4%) versus Asian (14.7%) or White (2.9%) patients. Conclusion: Our preliminary analyses suggest racial heterogeneity exists at the level of DNA methylation, gene expression and somatic mutation. We discovered that reporting on PDAC driver mutations is likely biased by the overrepresentation of White patient samples in the TCGA dataset – the largest publicly available dataset with data on sociocultural race. Given our preliminary results, further work to describe the DNA methylation and gene expression landscape in PDAC with respect to sociocultural race is imperative. However, until minority representation is improved in such biobanking efforts – the ability to perform molecular profiling of PDAC within those populations experiencing disparate incidence and outcomes remains underpowered. Citation Format: Haleigh Tianna Larson, Ankit Chhoda, Astrid Hengartner, Nesrin Hasan, Nensi Ruzgar, Sri Yalamanchi, John W. Kunstman, James J. Farrell, Anup Sharma, Nita Ahuja. Racial heterogeneity in the molecular landscape of pancreatic adenocarcinoma: A call for action [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-155.

146. Intact Sense of Taste and Smell During COVID-19 Infection Is Associated with Absence of of SARS-CoV-2 Spike Protein Antibody Responses within 3 Months of Symptomatic Illness

BackgroundAlthough studies show most COVID-19 survivors have post-infection immunity against SARS-CoV-2 that could prevent re-infection, there is still a need to identify the breadth of antibody (Ab) responses associated with clinical phenotypes. We characterized Ab profiles at the estimated peak of Ab diversity among adults with recovered SARS-CoV-2 infections and determined their relationships with clinical factors.MethodsFrom April-June 2020, 41 health system employees with PCR-confirmed symptomatic COVID-19 infection enrolled 8-10 weeks after symptom onset. Symptom questionnaires including baseline demographics, COVID-19 symptoms, disease severity, and disease duration were collected and plasma samples were assayed using a custom Luminex Multiplex platform (Figure 1) to measure the antibody response against 20 COVID-19 related antigens (Figure 2). Differences in Ab profile titers among different groups were tested using nonparametric t test and Benjamini-Hochberg adjustment for multiplicity. Associations were considered significant at FDR< 0.05. Figure 1: Description of the Luminex Serology Assay Figure 2: List of the COVID-19 Related Antigens and Controls MeasuredResultsMean age was 48 years (range 27-68), with 51% female, 37% White, 32% Black, 29% Asian, and 17% LatinX. Ab profiles (Figure 3) showed 100% cross-reactivity with related alpha and beta coronavirus, and 95% with SARS-CoV-1. 78% had Abs against SARS-CoV-2 nucleocapsid protein (NCP). However, 29% of patients had no immune response against the four spike protein epitopes. These participants also reported fewer symptoms, including no cases of anosmia/ageusia, suggesting mild illness. Anosmia/ageusia, fever, and cough associated significantly with higher Ab titers (Figure 4). ConclusionBroad immune responses to various SARS-CoV-2 and related antigens were found among a heterogeneous patient population. However, less than 3 months after symptom onset, protective Ab responses to SARS-CoV-2 spike proteins were not detected in nearly one-third of recovered patients, primarily with mild infection. Intact sense of smell and taste demonstrated the greatest association with loss of seroprotective SARS-CoV-2 Ab responses, which may be clinically useful to predict post-infection immunity. Next steps include comparing the magnitude of Ab responses following full series completion with mRNA vaccination among this cohort.Disclosures Robert Bencshop, PhD, Eli Lilly (Employee) Josh Poorbaugh, PhD, Eli Lilly (Employee) Ajay Nirula, MD/PhD, Eli Lilly (Employee, Shareholder) Lin Zhang, PhD, Eli Lilly and Company (Employee, Shareholder) Stephanie Beasley, BA, Eli Lilly (Employee)

Approximate distance correlation for selecting highly interrelated genes across datasets.

With the rapid accumulation of biological omics datasets, decoding the underlying relationships of cross-dataset genes becomes an important issue. Previous studies have attempted to identify differentially expressed genes across datasets. However, it is hard for them to detect interrelated ones. Moreover, existing correlation-based algorithms can only measure the relationship between genes within a single dataset or two multi-modal datasets from the same samples. It is still unclear how to quantify the strength of association of the same gene across two biological datasets with different samples. To this end, we propose Approximate Distance Correlation (ADC) to select interrelated genes with statistical significance across two different biological datasets. ADC first obtains the k most correlated genes for each target gene as its approximate observations, and then calculates the distance correlation (DC) for the target gene across two datasets. ADC repeats this process for all genes and then performs the Benjamini-Hochberg adjustment to control the false discovery rate. We demonstrate the effectiveness of ADC with simulation data and four real applications to select highly interrelated genes across two datasets. These four applications including 21 cancer RNA-seq datasets of different tissues; six single-cell RNA-seq (scRNA-seq) datasets of mouse hematopoietic cells across six different cell types along the hematopoietic cell lineage; five scRNA-seq datasets of pancreatic islet cells across five different technologies; coupled single-cell ATAC-seq (scATAC-seq) and scRNA-seq data of peripheral blood mononuclear cells (PBMC). Extensive results demonstrate that ADC is a powerful tool to uncover interrelated genes with strong biological implications and is scalable to large-scale datasets. Moreover, the number of such genes can serve as a metric to measure the similarity between two datasets, which could characterize the relative difference of diverse cell types and technologies.

Mycobiome Supporting Diet to Reduce Gastrointestinal (GI)Toxicity Associated with Autologous Stem Cell Transplant (ASCT) for Patients with Multiple Myeloma (MM)

Emerging data suggest healthy microbiome helps to protect against mucosal injury and inflammation. Dysbiosis results in biofilm formation in the gut which has been shown to be pro-inflammatory. MM patients potentially have significant dysbiosis result of long term corticosteroid use. Our group, previously showed that composition of microbiome presents at the pre-transplant period correlates with rate and degree of post-ASCT GI toxicities, neutropenic fever and neutrophilic engraftment among MM patients. Also, our data suggested a link between microbial communities at the count nadir and GI toxicity after high dose melphalan and ASCT.Mycobiome Supporting Diet (MSD) proposed in this study is designed to restructure the gut microbiome (both bacterial and fungal communities) and support optimal GI tract health. It combines elements from several diets (e.g., Paleo, low-carbohydrate, vegetarian, and Mediterranean) and excludes elements of these diets that have been specifically proven to increase pathogenic fungi in the human gut. Our group examined application of MSD among healthy volunteers between the ages of 30 and 70 who agreed to follow the MSD for 28 days on a prospective trial. At the end of the study period, subjects had a 1.7-fold decrease in the abundance of Proteobacteria (considered a red flag for inflammation), with levels reduced from 38.6% to 23.3% with significantly increased of beneficial species such as Faeclibacterium prausnitzii (up 35.8%) , Bifidobacterium adolescentis (up 61.6%) , Roseburia (up 57.5%) , Lactobacillus (up 77.6%) , and Bacteroides. Furthermore, Pathogenic bacteria decreased significantly, including Escherichia coli (down 74%), Bacteroides fragilis (down 45.3%), and Clostridium (down 55.7%). After the study, all participants with GI symptoms reported moderate or dramatic improvements. Two thirds of the participants who chose to track their weight lost significant weight (between two and 10 pounds) over the testing period. Thirty percent of the participants reported moderate or dramatically improved fatigue and higher energy levels.Given the association between baseline gut dysbiosis and post-transplant GI toxicities and availability of a highly curated diet to optimize the richness and diversity of gut microbiome communities, in this trial (ClinicalTrials.gov Identifier: NCT04685525) we sought to examine the feasibility of MSD diet among MM patients undergoing transplant by assessing its potential effect on decreasing post-transplant GI toxicities.Methods: The primary objective of this study is to evaluate the feasibility of MSD diet using patient's adherence to the MSD diet. The adherence will be assessed 3 times before transplant on days -21, -14 and -7. The MSD diet will deem feasible if at least 80% of patients showed adherence defined by 2 out of 3 assessment marked “more than half a time”. With sample size of 40 we will be able to estimate the adherence rate of 80% with 95% confidence interval of +/- 12%.To assess impact of MSD on micro- and mycobiome, a custom pipeline based on Greengenes V13_8 and Unite database V7.2 will be designed for the taxonomic classification of 16SrRNA and ITS sequences, respectively. Downstream data analysis will be performed using Qiime software. Statistical analysis will be performed using the statistical programming language R (version 3.3.0). Change across time in phyla and genus abundance at the community level will be assessed using the non-parametric multivariate distance-based analysis of variance using BC distance for dissimilarity metric along with its standardized binary form. Diversity will be analyzed in an unbiased manner using the Shannon diversity index, a measure of abundance taking into account microbial distribution. Richness will be also assessed, reflecting the microbial counts of the bacterial and fungal communities in each sample. Longitudinal analysis will be performed using all pair wise Multiple Comparison of Mean Ranks as implemented in the PMCMR plus R package version 1.2.0, employing Kruskal & Wallis test followed by Bonferroni-Dunn post-hoc adjustment. P <.05 will be considered statistically significant for all tests after correcting for multiple comparisons. Correction for multiple testing were performed using Benjamini-Hochberg adjustment method for multiple testing. [Display omitted] DisclosuresMalek: Sanofi: Other: Advisory Board; Bluespark Inc.: Research Funding; Amgen: Honoraria; Cumberland Inc.: Research Funding; Medpacto Inc.: Research Funding; Janssen: Other: Advisory board ; BMS: Honoraria, Research Funding; Takeda: Honoraria. Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau.

Adherence to Mediterranean diet and its associations with circulating cytokines, musculoskeletal health and incident falls in community-dwelling older men: The Concord Health and Ageing in Men Project

Mediterranean dietary patterns may exert favourable effects on various health conditions. This study aimed to determine associations of adherence to Mediterranean diet as well as its components, with circulating cytokine levels, musculoskeletal health and incident falls in community-dwelling older men. Seven hundred ninety-four (794) community-dwelling men with mean age 81.1±4.5 years, who participated in the five-year follow-up of the Concord Health and Ageing in Men Project (CHAMP) were included in the cross-sectional analysis, and 616 attended follow-up three years later. Adherence to Mediterranean diet was assessed using MEDI-LITE (literature-derived Mediterranean diet) score which was obtained using a validated diet history questionnaire. Twenty-four evaluable circulating cytokines were analyzed using Bio-Plex Pro Human Cytokine 27-plex Assay kit. Appendicular lean mass (ALM) and bone mineral density (BMD) were measured using dual-energy x-ray absorptiometry (DXA). Three-year changes in gait speed and hand grip strength were assessed by walking a 6-m course and using a dynamometer respectively and analyzed using linear mixed-effects models. Incident falls over three years were determined through telephone interviews every four months. Multivariable linear regression was utilized to determine the cross-sectional associations between MEDI-LITE scores and circulating cytokines, bone mineral density, ALM, and ALMBMI. Linear mixed-effects models were performed to estimate associations between MEDI-LITE scores and three-year change in hand grip strength and gait speed while negative binomial regression was applied to estimate associations between MEDI-LITE scores and three-year incident falls as well as associations between each MEDI-LITE component and three-year incident falls. Adjustments for multiple comparisons were performed using Benjamini-Hochberg adjustment for multiple testing. A higher MEDI-LITE score, indicating greater adherence to Mediterranean diet, was associated with higher appendicular lean mass adjusted for body mass index (ALMBMI) (β: 0.004kg; 95% CI: 0.000, 0.008), and lower incident falls rates (IRR: 0.94; 95% CI: 0.89, 0.99). Higher consumption of monounsaturated fatty acids (IRR: 0.76; 95% CI: 0.59, 0.98) and monounsaturated fatty acids to saturated fatty acids ratio (IRR: 0.72; 95% CI: 0.57, 0.90) were associated with 24%, and 28% lower falls risk in older men respectively. MEDI-LITE scores were not associated with BMD or physical function parameters. Adherence to a Mediterranean diet is associated with higher ALMBMI, and fewer falls in community-dwelling older men. Monounsaturated and saturated fatty acids were the most important contributors to the association between Mediterranean diet and falls risk.

The Influence of the COVID-19 Pandemic on the Use of Digital Technologies by Scientists: A Comparison Between Poland and Abroad

Purpose: Our research was performed to identify differences in the frequency of using digital technologies by scientists to support their research in the periods before, during, and after the COVID-19 pandemic Design/methodology/approach: A survey questionnaire was used and data were collected from 467 scientists from Poland and abroad, which were statistically analyzed. The non-parametric Kruskal–Wallis test was applied to reveal the differences in the frequency of digital technologies use between scientists in Poland and abroad in three periods (before, during, and after the COVID-19 pandemic). The non-parametric Friedman rank test and the post-hoc Conover test with Benjamini-Hochberg adjustment were used to assess the significant differences between three paired periods: before-during, before-after, and during-after the COVID-19 pandemic. For these periods, the association between the use of digital technologies and the types of research (basic or applied) conducted by scientists in Poland and abroad was also measured using Spearman’s rank correlation. Findings: Scientists from Poland and abroad differed in the use of all digital technologies before and after the COVID-19 pandemic. During the pandemic, the differences concerned only social media, owing to a similar increase in the use of both communication applications and e-learning platforms. The results demonstrated that there was a weak positive correlation between the use of all digital technologies and applied research by both groups of scientists for all paired periods. In Poland in particular, our research has confirmed a positive correlation between the use of communication applications and social media and basic research for two paired periods: before-during and during-after the pandemic. Research limitation/implications: The limitations of this study were primarily related to the sample size, which did not allow the results to be generalized to the entire population. Another limitation was that all scientists from outside Poland were assigned to one group, without division into countries or regions of the world. This, however, enabled the research scope to be narrowed and resulted in stressing the differences between Poland and the rest of the world. A further limitation that may affect the research results is the adopted 5-point Likert scale, which determines the possibility of making an analysis. Originality/value: This research contributes to knowledge about the adaptation of scientists in Poland and abroad to new conditions resulting from the COVID-19 pandemic regarding the frequency of digital technology use in basic and applied research. The significant differences found in the frequency of digital technology use between the three paired periods (before-during, before-after, and during-after the pandemic) have the potential to encourage research into their permanence.

Low BMI (< 10th percentile) increases complications and readmissions after posterior spinal fusion in adolescent idiopathic scoliosis.

While obesity has been shown to predict negative outcomes following PSF in AIS patients, less is known about the effects of low BMI. We sought to elucidate the impact of low BMI on 30-day outcomes in this population. Adolescent idiopathic scoliosis patients undergoing PSF were identified using the 2015-17 ACS-NSQIP-Pediatric database. Patients were placed in underweight (UW, < 10th percentile) and normal weight (NW 10-90th percentile) cohorts based off CDC BMI-to-age growth charts. Demographics, comorbidities, intra-, and postoperative factors were compared via univariate analysis with Benjamini-Hochberg adjustment. Multivariable logistic regression models were generated to assess UW status as a predictor of complications. Two thousand seven hundred and ninety-nine AIS patients undergoing PSF (NW = 2517, UW = 282) were identified. UW patients were older (15.6 vs. 14.7years), less female dominant (62.4% vs. 79.5%), and had more pulmonary (2.5% vs. 0.4%) and minor cardiac comorbidities (6% vs. 1.7%) compared to NW patients (p < 0.001). UW patients had a greater percentage blood loss (6.7% vs. 5.3% of total blood volume, p < 0.001) and higher complication (3.9% vs. 1.4%, p = 0.008), pneumonia (1.4% vs. 0.1%, p = 0.006), and readmission (3.5% vs. 1.2%, p = 0.001) rates compared to NW patients. UW status was a predictor of ≥ 15% blood volume loss (adjusted OR = 2.65; 95% CI = 1.76-3.97; p < 0.001), pneumonia (aOR = 6.57; 95% CI = 1.80-24.00; p = 0.004), and hospital readmission (aOR = 2.47; 95% CI = 1.02-6.01; p = 0.046). There is a higher occurrence of complications in UW AIS patients undergoing PSF. Low BMI is an independent predictor of ≥ 15% blood loss, pneumonia, and readmissions. Like their overweight counterparts, underweight AIS patients have an increased postoperative risk for negative complications.

Early Interleukin-22 and Neutrophil Proteins Are Correlated to Future Lung Damage in Children With Cystic Fibrosis.

Cystic Fibrosis (CF) lung damage begins early in life. Lung function decline is associated with pulmonary infections, neutrophil infiltration and inflammation. In CF, neutrophils have an altered phenotype. In this pilot study, we aimed to determine if signals of dysfunctional neutrophil responses were evident early in life and whether these signals may be associated with lung damage in later childhood. We examined the pulmonary protein profiles of 14 clinical stable infants and pre-school children with CF employing the aptamer-based affinity platform, SOMAscan®. High resolution computed tomography (HRCT) was performed on all children after age 6 years and Brody score calculated. A Spearman's rank order correlation analysis and Benjamini-Hochberg adjustment was used to correlate protein concentrations in early life to Brody scores in later childhood. Early life concentrations of azurocidin and myeloperoxidase, were positively correlated with Brody score after age 6 (p = 0.0041 and p = 0.0182, respectively). Four other neutrophil associated proteins; Complement C3 (p = 0.0026), X-ray repair CCP 6 (p = 0.0059), C3a anaphylatoxin des Arginine (p = 0.0129) and cytokine receptor common subunit gamma (p = 0.0214) were all negatively correlated with Brody scores. Interestingly, patients with more severe lung damage after age 6 had significantly lower levels of IL-22 in early years of life (p = 0.0243). IL-22 has scarcely been reported to have implications in CF. Identification of early biomarkers that may predict more severe disease progression is particularly important for the future development of early therapeutic interventions in CF disease. We recommend further corroboration of these findings in prospective validation studies.

Integrative analysis of genetic and clinical risk factors for bone loss in a Korean population.

The relative contribution of genetic and clinical factors for bone loss is not well known. This study aimed to investigate the annualized percentage change in total hip bone mineral density (BMD) and the genetic and clinical risk factors for bone loss in a Korean prospective cohort study over a 6-year period. We included 645 men aged ≥50years and 683 postmenopausal women who had repeated BMD testing between 2007 and 2014. The association between covariates and annualized percentage change in hip BMD was analyzed through the multivariate linear regression analysis. A total of 2614 single-nucleotide polymorphisms (SNPs) from 23 known BMD-related candidate genes and genome-wise association study were investigated. Hip bone loss increased more rapidly in women than in men with advancing age. Hip bone loss in men increased with lean mass (LM) loss (%/year) (P<0.001) and current smoking (P=0.024) and decreased with increasing waist circumference (WC) (P<0.001), alcohol consumption (P=0.049), and increase in red blood cell counts (P=0.031). Decreasing WC (P=0.009), LM loss (%/year) (P<0.001), and years since menopause ≤ 3years (P=0.003) significantly correlated with hip bone loss in women aged 45-59years. Hip bone loss in women aged ≥60years increased with advancing age (P=0.012), alcohol consumption (P=0.028), LM loss (%/year) (P=0.031), and fat mass loss (%/year) (P<0.001) and decreased with increasing WC (P=0.025). LRP5 rs498830 (β=0.127, P=0.007) and TNFSF11 rs7325635 (β=0.146, P=0.001) were the top SNPs related to hip bone loss in men and postmenopausal women, respectively. However, none of the SNPs were associated with hip bone loss after Benjamini-Hochberg adjustment. In this study, decreasing WC and LM were significant risk factors for hip bone loss in both men and women. Those factors were also identified that had sex-specific or age-specific effects on hip bone loss. None of the SNPs were associated with hip bone loss after multiple testing adjustments. The understanding of the modifiable factors contributing to bone loss has been broadened, and this may have implications such as in developing individualized preventive strategy. Further studies are needed to better predict the risk for bone loss in men and women.

Educational Studies Examining Knowledge of Substance Use Disorders and Career Aspirations Among Medical Trainees in an Inner-City Hospital.

Gaps in addiction medicine training are a reason for poor substance use care in North America. Hospital addiction medicine consult services (AMCS) provide critical medical services, including screening and treatment of substance use disorders. Although these programs often feature an educational component for medical learners, the impact of AMCS teaching on objective knowledge and career aspirations in addiction medicine has not been well described. The authors report findings from two sequential studies conducted at a large academic hospital in Vancouver, Canada. The first study assessed the impact of an AMCS clinical rotation on medical trainee addiction medicine objective knowledge using an online survey of 6 true/false questions before and after the rotation. The second study examined the impact of an AMCS rotation on career aspirations using 4 seven-point Likert-type questions. One-sample t tests on mean differences (MD) with Benjamini-Hochberg adjustment for multiple comparisons were employed for statistical analyses. Between May 2017 and June 2018, knowledge scores were significantly higher postrotation (MD = 4.78, standard deviation [SD] = 19.5, P = 0.034) among 115 medical trainees. Between July 2018 and July 2019, aspirations to practice addiction medicine were significantly more favorable postrotation (MD = 3.48, SD = 3.15, P < 0.001) among 101 medical trainees. AMCS rotations appear to improve addiction medicine knowledge and aspirations to practice addiction medicine among medical trainees. Larger-scale evaluations and outcomes research on integrating substance use disorders teaching in these settings will help move the discipline forward.

AGE-RELATED PREGNANCY LOSS IS LARGELY OVERCOME WITH SINGLE EUPLOID EMBRYO TRANSFER

Oocyte aneuploidy is significantly associated with increasing maternal age and is the primary cause of reproductive failure including pregnancy loss for women of advanced maternal age (AMA; ≥38 years). Preimplantation genetic testing for aneuploidy (PGT-A) has been shown to improve IVF live birth outcomes from embryo transfer for AMA infertility patients. The aim of this study was to evaluate the efficacy of single euploid embryo transfers to reduce the impact of AMA on pregnancy loss. Retrospective large cohort study A total of 3,773 single euploid transfers (SET) from 2010-2019 at a large IVF clinic, which underwent PGT-A at a single Genetics laboratory, were included in this cohort analysis. Donor oocyte and gestational carrier cycles were excluded. Groups were defined based on maternal age at the time of oocyte retrieval: <35 years (n=1,261 SETs), 35-37 years (n=1,074 SETs), 38-40 years (n=950 SETs), 41-42 years (n=397 SETs) and >43 years (n=91 SETs). Outcome measures included clinical pregnancy (visualized gestational sac and fetal pole), miscarriage (visualized fetal heart tone followed by loss) and live birth. Statistical analysis was performed where appropriate with Fisher’s exact, Kruskal-Wallis and Benjamini-Hochberg adjustment, significance at p < 0.05. Clinical pregnancy and live birth rates significantly decreased with AMA of ≥38 years (Table 1; *P<0.001). In contrast, miscarriage was not significantly different across the maternal age groups, including for AMA women (≥38 years). Only 2.4% of sustained implantations resulted in monozygotic twinning with monozygotic twinning 2.5x more likely to result in a pregnancy loss (p < 0.05). This large cohort analysis of SETs has revealed that the age-related increase in pregnancy loss associated with aneuploidy has been largely overcome with PGT-A and the selection of euploid embryos for transfer. A small but significant decrease in live birth outcomes still remains for AMA women undergoing infertility treatment and represents the additional embryonic and maternal factors associated with reproductive success.Tabled 1<35 Years35-37 Years38-40 Years41-42 Years43+ Yearsn=1,261 SETsn=1,074 SETsn=950 SETsn=397 SETsn=91 SETsClinical Pregnancy Rate68.0%70.0%63.3%*62.0%*61.0%*MAB Rate6.3%6.6%4.7%5.3%3.6%Live Birth Rate63.7%65.4%60.3%*58.7%*59.3%* Open table in a new tab

A-131 Clinical Utility of the Child &amp; Adolescent Memory Profile in Children with TBI

Abstract Objective To evaluate the sensitivity of The Child and Adolescent Memory Profile (ChAMP), a relatively new test of learning and memory, to traumatic brain injury (TBI). Method The ChAMP was administered to 61 6–16 year-old children with TBI within 1–12 months post injury. The sample was 64% male and 75% Caucasian, with a median parental level of education of 13 years. Twenty-nine children had uncomplicated mild TBI whereas 32 children had either intracranial lesions on neuroimaging or coma of at least 24 hrs, or both. The findings from the complete TBI group were compared to those from a demographically matched control group, obtained from the ChAMP standardization sample. Results Within the TBI group, the Visual Memory, Immediate Memory, Total Memory and Screening Index scores all demonstrated statistically significant correlations with length of coma. After applying a Benjamini-Hochberg adjustment to correct for the effect of multiple comparisons, the performance of the matched control group was still statistically significantly better than that of the children with TBI on all of the ChAMP Index scores. Effect sizes ranged from small to medium. At the subtest level, Places and Places Delayed showed the greatest group differences. Conclusion These findings supported the clinical utility of the ChAMP in the evaluation of learning and memory in children with TBI.

OP0044 WHOLE KIDNEY TRANSCRIPTOMIC ANALYSIS OF FORMALIN-FIXED PARAFFIN-EMBEDDED LUPUS NEPHRITIS KIDNEY BIOPSY TISSUE USING THE NANOSTRING NCOUNTER PLATFORM

Background:There is an ongoing effort to elucidate the molecular pathways that are key to kidney injury in lupus nephritis (LN). One approach is to study the transcriptome utilising kidney tissue obtained during diagnostic renal biopsy [1]. In clinical practice the most common tissue that is surplus to diagnostic requirements is formalin-fixed paraffin-embedded (FFPE) tissue. However, due to RNA degradation, transcriptomic analysis has been sub-optimal and challenging using standard procedures. The NanoString technology platform has the advantage that reliable detection of transcripts can be achieved even with degraded RNA. In this study we explored the utility of NanoString technology in identifying transcripts in RNA isolated from archival FFPE kidney biopsy sections in a cohort of patients with LN.Objectives:To explore the utility of the NanoString platform in elucidating a renal transcriptomic signature in formalin-fixed paraffin-embedded Lupus Nephritis kidney biopsy tissue.Methods:We utilised well defined Class III (n=11); Class IV (n=22) and Class V (n=24) LN FFPE kidney biopsies from female patients attending the Imperial College Healthcare NHS Trust. We excluded biopsies with mixed lesions or chronic lesions (i.e. significant glomerular scarring). Kidney biopsies from patients with Thin Basement Membrane (TBM; n=14) disease were used as controls. Six 10 micron thick sections were obtained from each biopsy and RNA isolated using the Qiagen RNeasy FFPE Kit. 100 micrograms of RNA was used for the detection of transcripts. We used the NanoString PanCancer immune profiling panel (770 transcript probes) and an additional 30 custom designed probes, enabling us to detect 800 transcripts, including 40 reference genes. Transcript analysis was performed according to manufacturer’s instructions using the NanoString nSolver software. When analysing differential gene expression (DGE) we used Benjamini-Hochberg adjustment to account for multiple testing. The threshold for statistical significance was an adjusted P value of 0.05 (5% false discovery rate).Results:Transcriptomic data passing NanoString nSolver quality control metrics was obtained from all sections. Notably sections included biopsies up to 16 years old (range: 1-16 years). Our transcript panel contained several Type I interferon (IFN) responsive genes, including sialic acid-binding Ig-like lectin 1 (Siglec-1). We detected a type I IFN signature using 8 IFN-responsive transcripts in 39 (68.4%) of the LN biopsies but in none of the TBM biopsies. This signature was present in Class III (n=9, 81.8%), Class IV (n=16, 72.7%) and Class V (n=14, 58.3%) LN samples. When we performed DGE analysis using TBM as the baseline we detected significantly increased expression across the classes (Class III = 202; Class IV = 357 and Class V = 237 differentially expressed transcripts, Figure 1).Conclusion:We have successfully identified transcriptomic signatures in RNA samples derived from a relatively large cohort of FFPE LN samples. Consistent with published reports we could detect a type I IFN signature in the LN kidney tissue [1]. Consistent with a recent study [1], we detected increased expression of OPN (osteopontin) and FN1 (fibronectin-1) in proliferative (Class III and IV) but not Class V LN. We are now performing clinical correlations to determine if the differentially expressed transcripts are clinically informative.

Urinary proteomics links keratan sulfate degradation and lysosomal enzymes to early type 1 diabetes.

Diabetes is the leading cause of end-stage renal disease worldwide. Our understanding of the early kidney response to chronic hyperglycemia remains incomplete. To address this, we first investigated the urinary proteomes of otherwise healthy youths with and without type 1 diabetes and subsequently examined the enriched pathways that might be dysregulated in early disease using systems biology approaches. This cross-sectional study included two separate cohorts for the discovery (N = 30) and internal validation (N = 30) of differentially excreted proteins. Discovery proteomics was performed on a Q Exactive Plus hybrid quadrupole-orbitrap mass spectrometer. We then searched the pathDIP, KEGG, and Reactome databases to identify enriched pathways in early diabetes; the Integrated Interactions Database to retrieve protein-protein interaction data; and the PubMed database to compare fold changes of our signature proteins with those published in similarly designed studies. Proteins were selected for internal validation based on pathway enrichment and availability of commercial enzyme-linked immunosorbent assay kits. Of the 2451 proteins identified, 576 were quantified in all samples from the discovery cohort; 34 comprised the urinary signature for early diabetes after Benjamini-Hochberg adjustment (Q < 0.05). The top pathways associated with this signature included lysosome, glycosaminoglycan degradation, and innate immune system (Q < 0.01). Notably, all enzymes involved in keratan sulfate degradation were significantly elevated in urines from youths with diabetes (|fold change| > 1.6). Increased urinary excretion of monocyte differentiation antigen CD14, hexosaminidase A, and lumican was also observed in the validation cohort (P < 0.05). Twenty-one proteins from our signature have been reported elsewhere as potential mediators of early diabetes. In this study, we identified a urinary proteomic signature for early type 1 diabetes, of which lysosomal enzymes were major constituents. Our findings highlight novel pathways such as keratan sulfate degradation in the early kidney response to hyperglycemia.

Effect of chemokine signaling signatures on resolving discrepancy between TMB and checkpoint expression.

3131 Background: Tumor mutation burden (TMB) and PD1/L1 expression are independent biomarkers for immune checkpoint blockade therapy, as seen in the Checkmate227 trial. Here we explore whether chemokine activity, an intermediate step between neoantigen presentation and immune-infiltration, can resolve this lack of association between existing biomarkers. We further use this novel biomarker to corroborate recent findings from Crowther et al. for a role of MHC class 1-related gene ( MR1) downregulation in immune evasion. Methods: 1,395 clinical samples from the NantHealth database with matched tumor:normal whole exomes and deep whole-transcriptomic sequencing (&gt; 200M reads) were available for analysis. The most common indications in the cohort were Breast (18%), Colon (9.8%), Lung (7.8%), Soft-tissue/Sarcomas (7.7%), and Pancreatic (6.1%). TMB was calculated by counting non-synonymous exonic mutations as per Rizvi, 2015. Immune-infiltration and chemokine signaling were inferred from RNAseq expression of published immune-cell-specific genesets (Bindea, 2013) and chemokine ligands (Nagarsheth, 2017) respectively. Significant associations between TMB, chemokine activity, immune-infiltration, and checkpoint expression were analyzed by ranksums test and corrected for multiple-hypothesis testing using Benjamini-Hochberg adjustment. Results: As expected, TMB and PD1/L1 mRNA expression were not correlated in this cohort (r = 0.08 and r = 0.07 respectively). 36.3% of patients classified as highly immune-infiltrated by unsupervised clustering of immune-cell scores, and this subgroup significantly overexpressed all 11 targetable checkpoint genes analyzed including PD1, PDL1, CTLA4, IDO1, and VISTA (adj. p 9.7e-68 to 4e-168). There was no association between immune-infiltrated samples and TMB (t = 0.9, p = 0.35). Twice as many patients classified as chemokine-active (70.0%) and there was significant agreement between immune-infiltrated and chemokine-active patients (OR = 34.8, p = 6.5e-81). Interestingly, there was a weak but significant association between high chemokine-activity and increased TMB (t = 3.3, p = 0.001). Within patients that were chemokine-active but lacked immune-infiltration, MR1 expression was significantly depleted (t = -10.7, p = 1e-26). Conclusions: Chemokine signatures can help resolve discordance between TMB and checkpoint expression. Analysis of discordance between chemokine-active but immune-depleted tumors may aid in identifying targets for converting from cold to hot tumor microenvironments.

Pediatric Clinician Comfort Discussing Diagnostic Errors for Improving Patient Safety: A Survey.

Introduction:Meaningful conversations about diagnostic errors require safety cultures where clinicians are comfortable discussing errors openly. However, clinician comfort discussing diagnostic errors publicly and barriers to these discussions remain unexplored. We compared clinicians’ comfort discussing diagnostic errors to other medical errors and identified barriers to open discussion.Methods:Pediatric clinicians at 4 hospitals were surveyed between May and June 2018. The survey assessed respondents’ comfort discussing medical errors (with varying degrees of system versus individual clinician responsibility) during morbidity and mortality conferences and privately with peers. Respondents reported the most significant barriers to discussing diagnostic errors publicly. Poststratification weighting accounted for nonresponse bias; the Benjamini–Hochberg adjustment was applied to control for false discovery (significance set at P < 0.018).Results:Clinicians (n = 838; response rate 22.6%) were significantly less comfortable discussing all error types during morbidity and mortality conferences than privately (P < 0.004) and significantly less comfortable discussing diagnostic errors compared with other medical errors (P < 0.018). Comfort did not differ by clinician type or years in practice; clinicians at one institution were significantly less comfortable discussing diagnostic errors compared with peers at other institutions. The most frequently cited barriers to discussing diagnostic errors publicly included feeling like a bad clinician, loss of reputation, and peer judgment of knowledge base and decision-making.Conclusions:Clinicians are more uncomfortable discussing diagnostic errors than other types of medical errors. The most frequent barriers involve the public perception of clinical performance. Addressing this aspect of safety culture may improve clinician participation in efforts to reduce harm from diagnostic errors.

Inter and intra specific variation in echolocation signals among odontocete species in the Northwest Atlantic, the Temperate Pacific and Hawaii

Odontocete species use echolocation signals (clicks) to forage and navigate. The aim of this study is to explore inter- and intra-specific variation in clicks among odontocete species in the Northwest Atlantic, Temperate Pacific, and Hawaii. Clicks were examined for seven species of odontocetes—bottlenose dolphins, common dolphins, striped dolphins, rough-toothed dolphins, pilot whales, Risso’s dolphins, and Cuvier’s beaked whales. Specially developed PAMGuard tools were used to automatically measure a suite of click parameters. Seven parameters were compared within and between species; duration, 10 dB bandwidth, 3 dB bandwidth, center frequency, peak frequency, sweep rate, and number of zero crossings. Significant differences in duration, center, and peak frequency were evident between species within study areas (Dunn’s test with Benjamini-Hochberg adjustment <0.05). Geographic variation in click parameters between the three study regions was also examined. Results showed statistically significant pair-wise differences between geographic regions for almost all echolocation click parameters and species (Dunn’s test with Benjamini-Hochberg adjustment <0.05). Results suggest species-specific differences in clicks among odontocetes and indicate that geographic variation exists for multiple species. The ecological significance of these findings will be discussed along with implications for classifier development.

Rectovaginal Colonization With Pathogenic Escherichia coli During Pregnancy And Neonatal Outcomes.

PurposeThe role of pathogenic Escherichia coli colonization in asymptomatic pregnant women is not well understood. The purpose of this work was to determine the prevalence, antimicrobial susceptibility, and neonatal outcomes of pathogenic E. coli colonization in pregnant women.Patients and methodsA total of 137 women from southern Taiwan with singleton pregnancies were enrolled between March 2016 and June 2017. The women were prospectively screened for E. coli colonization in the rectovaginal region during prenatal examination. The exclusion criteria are twin pregnancy of the mother and major anomaly of the neonate. All E. coli isolates were identified as either pathogenic or commensal strains, and their susceptibility to various antimicrobials was investigated. Clinical data of the infants were retrieved from their medical records.ResultsResults showed that 35.8% of asymptomatic pregnant women had pathogenic E. coli colonization in the rectovaginal region. Neonates born to such mothers showed significant morbidities, including hospitalization (OR= 3.74, 95% CI= 1.18~11.87), hyperbilirubinemia (OR= 2.81, 95% CI= 1.24~6.38), and gastrointestinal symptoms (OR= 5.53, 95% CI= 1.39~21.94). Maternal colonization with pathogenic E. coli at rectoanal site was a risk factor for neonatal hyperbilirubinemia after Benjamini–Hochberg (BH) adjustment (52% vs 24%, adjusted P= 0.048).ConclusionThe prevalence of pathogenic E. coli colonization in Taiwanese asymptomatic pregnant women was high, and the neonates born to colonized mothers exhibited potential neonatal morbidities. Larger studies are necessary to confirm these findings.