Bonferroni-adjusted P-value Research Articles

Joint Secondary Transcriptomic Analysis of Non-Hodgkin's B-Cell Lymphomas Predicts Reliance on Pathways Associated with the Extracellular Matrix and Robust Diagnostic Biomarkers.

Approximately 450,000 cases of Non-Hodgkin's lymphoma are annually diagnosed worldwide, resulting in ~240,000 deaths. An augmented understanding of the common mechanisms of pathology among larger numbers of B-cell Non-Hodgkin's Lymphoma (BCNHL) patients is sorely needed. We consequently performed a large joint secondary transcriptomic analysis of the available BCNHL RNA-sequencing projects from GEO, consisting of 322 relevant samples across ten distinct public studies, to find common underlying mechanisms and biomarkers across multiple BCNHL subtypes and patient subpopulations; limitations may include lack of diversity in certain ethnicities and age groups and limited clinical subtype diversity due to sample availability. We found ~10,400 significant differentially expressed genes (FDR-adjusted p-value < 0.05) and 33 significantly modulated pathways (Bonferroni-adjusted p-value < 0.05) when comparing BCNHL samples to non-diseased B-cell samples. Our findings included a significant class of proteoglycans not previously associated with lymphomas as well as significant modulation of genes that code for extracellular matrix-associated proteins. Our drug repurposing analysis predicted new candidates for repurposed drugs including ocriplasmin and collagenase. We also used a machine learning approach to identify robust BCNHL biomarkers that include YES1, FERMT2, and FAM98B, which have not previously been associated with BCNHL in the literature, but together provide ~99.9% combined specificity and sensitivity for differentiating lymphoma cells from healthy B-cells based on measurement of transcript expression levels in B-cells. This analysis supports past findings and validates existing knowledge while providing novel insights into the inner workings and mechanisms of transformed B-cell lymphomas that could give rise to improved diagnostics and/or therapeutics.

Participation in the Special Supplemental Nutrition Program for Women, Infants, and Children and Dietary Intake in Children: Associations With Race and Ethnicity

Establishing healthy dietary intake in pediatric populations is important for prevention of chronic disease across the lifespan. Federal nutrition assistance programs can support the dietary intake of U.S. children. The objective of this study was to assess the relationship between Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) participation status and dietary intake within racial and ethnic groups. Dietary intake of children aged 2-4 years in the cross-sectional National Health and Nutrition Examination Survey 2011-2016 was analyzed in 2021. Multivariable linear regression was used to compare stratum-specific mean estimates for nutrient and food group intake of children participating in Special Supplemental Nutrition Program for Women, Infants, and Children (reference group) with those of nonparticipants who were income eligible and income ineligible (i.e., above income limits) for the WIC program. Significance was set to Bonferroni-corrected p-values. Hispanic WIC participants consumed less added sugar (8.9 [SE=0.5] teaspoons) than their higher-income counterparts (14.6 [SE=1.5] teaspoons, p<0.001). Hispanic WIC participants also consumed more fiber (13.0 [SE=0.6] grams) than income-eligible (11.4 [SE=0.7] grams, p=0.032) and income-ineligible (i.e., higher-income, 9.4 [SE=1.3] grams, p=0.019) nonparticipants, but this was not significant at the Bonferroni-adjusted p-value of 0.01. No differences in dietary intake were observed by WIC participation status for non-Hispanic White and non-Hispanic Black children. Participation in WIC was associated with healthier dietary outcomes among Hispanic children; however, dietary intake of White and Black children was comparable by WIC participation status. Federal nutrition assistance programs should support sound nutrition, an important factor in reducing the risk of chronic disease, in all groups.

Efficacy of Bladder Intravesical Chemotherapy with Three Drugs for Preventing Non-Muscle-Invasive Bladder Cancer Recurrence.

Epirubicin, gemcitabine, and pirarubicin are widely used as first-line drugs for intravesical chemotherapy to prevent tumor recurrence after transurethral bladder tumor resection for non-muscle-invasive bladder cancer (NMIBC). However, which drug is better is less discussed. A total of 335 NMIBC patients administered intravesical chemotherapy underwent transurethral bladder tumor resection (TURBT) in our hospital from October 2015 to October 2019. After TURBT, all the patients received standard intravesical chemotherapy. Through clinical data collection and telephone follow-up, the tumor recurrence and adverse reactions of all patients after bladder perfusion treatment were counted. Recurrence was defined as new tumor appearance in the bladder. Of the 335 patients who underwent intravesical chemotherapy, 109 patients received epirubicin and 114 patients and 112 patients were given gemcitabine and pirarubicin, respectively. According to the general information of the patients, the patients were divided into intermediate-risk and high-risk bladder cancer and compared separately. There was no statistical difference in clinical and pathological features between different groups (P > 0.05). The recurrence rate of intermediate-risk bladder cancer patients shows no difference between three groups (P > 0.05). As for the high-risk bladder cancer patients, it is found that the 1-year recurrence rate between three groups was not statistically significant (P > 0.05), whereas the 2-year recurrence rate of patients given gemcitabine (9.87%) was significantly lower than that of epirubicin (25.37%) and pirarubicin (24.32%), and the difference was statistically significant (P < 0.017, Bonferroni adjusted P value). The Kaplan–Meier survival curves showed that the recurrence-free survival rate of patients received gemcitabine was significantly higher than that of the other two groups. Comparing the incidence of adverse reactions during the infusion of the three groups of patients, the differences were not statistically significant (P > 0.05). In patients with high-risk non-muscle-invasive bladder cancer, the application of gemcitabine intravesical chemotherapy is related with a relatively lower recurrence rate but similar incidence of adverse reactions.

Abstract 13101: Bleeding Complications in Patients Undergoing Percutaneous Coronary Intervention With Intra-Aortic Balloon Pump and/or Impella Support: A System Wide Analysis

Background: Mechanical circulatory support (MCS) devices are used to provide temporary hemodynamic support in patients undergoing percutaneous coronary interventions (PCI). Currently, the most used percutaneous devices are the intra-aortic balloon pump (IABP) and the Impella micro-axial flow device. Aim: To assess bleeding complications associated with IABP and/or Impella in patients undergoing PCI. Methods: Between 12/2010 and 03/2018 a total of 883 patient underwent PCI with MCS at 6 hospitals in our system. Patients were divided into three groups: IABP (n=679), Impella (n=171) and IABP with Impella (n=33). Bleeding complications were classified according to the Bleeding Academic Research Consortium (BARC). BARC Type 4 (coronary bypass grafting-related) and BARC Type 5 (fatal bleeding) bleeding events were excluded. Chi-square tests and logistic regression were utilized with p&lt;0.05 significance level. Multiple pairwise comparisons using Bonferroni-adjusted p-value threshold of p&lt;0.0167 for level of significance was also performed. A multiple variable analysis will be presented. Results: Clinical characteristics, bleeding complications and in-hospital outcomes are shown in the Table. There were significant differences in these variables except age and gender among the three groups. A minority of patients (4%) were treated simultaneously with both devices, however 45% of these patients had a significant bleeding event and 33% died in the hospital. No significant difference in bleeding complications between IABP and Impella (each alone) was found (p=0.38). Conclusions: In patients undergoing PCI, use of a combination of IABP and Impella was associated with significantly higher rate of intermediate or major bleeding complications when compared with patients treated with either device alone. Furthermore, these patients had significantly higher in-hospital mortality rates.

MEFV E148Q variant is more associated with familial Mediterranean fever when combined with other non-exon 10 MEFV variants in Japanese patients with recurrent fever

Objective To investigate the genetic characteristics of one of the MEFV gene variants, p.Glu148Gln (E148Q), in patients with familial Mediterranean fever (FMF) and examine its significance in Japanese patients with recurrent fever. Methods The clinical phenotype and genomic variants of systemic autoinflammatory diseases (SAIDs), including MEFV, were analyzed in 211 Japanese patients with recurrent fever. Genetic analysis was performed via next-generation sequencing of exons, including exon-intron boundaries. Results Twelve patients met the diagnostic criteria for SAIDs other than FMF. Considering 199 patients with recurrent fever, 137 cases (68.8%) were clinically diagnosed with FMF. Although Bonferroni-adjusted p-value did not reach significance level, the group containing heterozygous E148Q and other variants tended to be at higher risk of developing the FMF phenotype (nominal p = .036) than the group with heterozygous E148Q only. Comparison between the group with heterozygous E148Q and other variants and the heterozygous group containing non-E148Q showed no statistically significant difference in FMF phenotype expression (nominal p = 1.00). Conclusion Patients with heterozygous E148Q and other variants exhibited higher expression of FMF phenotype than those with heterozygous E148Q only, and suggested that other variants than E148Q as well as exon 10 variants might contribute to the FMF phenotype.

Hereditary cancer testing in an ethnically diverse U.S. population.

10579 Background: The clinical utility of hereditary cancer multigene testing is well-established. Most testing has been performed in the White European population, with a relative shortage of data in other ethnic groups. Evaluation of hereditary cancer variants within diverse ethnic populations is important to drive accurate variant interpretation. This study aims to review the outcomes of hereditary cancer testing in an ethnically diverse U.S. population. Methods: We conducted a retrospective analysis of 8,888 test results from a 31-gene hereditary cancer test using next-generation sequencing with copy number variant analysis. Results were separated into seven categories based on the ethnicity selected on the test requisition: African American (AA), Asian (A), Ashkenazi Jewish (AJ), Hispanic (H), White (W), Other (O), and Unknown (U). O was used for any handwritten ethnicity or if multiple ethnicities were selected and U if no ethnicity was chosen. We quantified the number of negative, positive (pathogenic or likely pathogenic (P/LP) variant) and variant of uncertain significant (VUS) results for each ethnic group. We tallied the gene and variant for each result with a positive, negative or VUS. We used a Fisher's Exact test and Bonferroni-adjusted p-values to account for multiple hypothesis testing. Results: Of the 8,888 orders reviewed, 45% were non-White ethnic groups. The P/LP variant rate was lower for AA (4%, p=2e-04) compared to W (9%). The VUS rate was higher for O, AA and A (48%, 56%, and 57%; p=0.0045, 3.1e-17 and 4.8e-06, respectively), compared to 38% in W. Lower negative rates were found in A and AA (37% and 40%; p=0.00024 and 9.4e-10, respectively), and trending lower in O (46%, p=0.0097), compared to 58% for W. The VUS rate for H is 41% (p value = 0.095). Conclusions: Our results suggest that non-Whites may be at a disadvantage when it comes to hereditary cancer multigene testing due to the higher rate of VUS results. The inverse correlation between the overall rates of VUS and negative results when comparing these populations suggests there may be limited variant information for the non-White population in medical literature and available databases. This underrepresentation may make it more difficult to accurately characterize a variant. Despite the small sample size, these findings are consistent with previous publications; however, gene specific outcomes could not be evaluated. This finding suggests that providers could give these patients uninformative results more often, which has potential to impact screening protocols for these families. More research is needed to understand the impact of variant classification across ethnicities to decrease health disparities.

Genome-wide association study for postweaning weight traits in Lori-Bakhtiari sheep.

Marker-assisted selection is an effective method in novel animal breeding programs. This study was conducted to perform a genome-wide association study to detect candidate genes and quantitative trait loci associated with postweaning weight traits in meat-type sheep. Body weight records were collected during 29 years (1989 to 2017) in Lori-Bakhtiari sheep flock of the Shooli Breeding Station in Iran. A total of 132 animals were selected based on estimates of breeding values (EBVs) for body weight, using two-tailed and random selection strategies. Genomic DNA was extracted from whole blood samples. The samples were genotyped using Illumina OvineSNP50 BeadChip. De-regressed EBVs for postweaning body weight traits were used as pseudo-phenotypes in a genome-wide association study. One SNP on chromosome 10 (rs406324209) and two SNPs on chromosome 13 (rs401963094 and rs418761613) were significantly (Bonferroni-adjusted p-values < 0.05) associated with postweaning body weight traits. The significant variants accounted for 0.20% and 0.48% of the total genetic variances for 6- and 9-month body weights, respectively. Genomic heritabilities estimated for 6-, 9- and 12-month weights and postweaning weight gain were 0.28 ± 0.34, 0.35 ± 0.29, 0.37 ± 0.34, and 0.16 ± 0.33, respectively. Two significant SNPs were located within the ATP8A2 and PLXDC2 genes, on chromosomes 10 and 13, respectively. Based on the known gene ontologies, both ATP8A2 and PLXDC2 could be considered as candidate genes for postweaning body weight traits.

Reference values for the short forms of the Singapore Caregiver Quality of Life Scale

PurposeThe 15- and 10-item short forms of the Singapore Caregiver Quality of Life Scale (SCQOLS-15 and SCQOLS-10) were recently developed as a quick assessment of caregiver quality of life. Reference values describing the distribution of the total and domain scores are available for the full-length version, but they are not yet available for the short forms. This study aimed to estimate the reference values for the short forms.MethodsData from a cross-sectional survey of 612 family caregivers of patients with advanced cancer in Singapore were fitted in quantile regression models. Percentiles were estimated by regressing the short forms’ scores on caregiver characteristics. Classification by the reference values for the short forms and the full-length version were compared and agreement was evaluated.ResultsThe caregiver’s role in caring for the patient and the patient’s performance status were associated with the percentiles of the total scores and most domain scores (each Bonferroni-adjusted p-value, PB, < 0.05). Higher-educated caregivers were categorized into higher percentiles according to the SCQOLS-15 and SCQOLS-10 total scores and the SCQOLS-15 Mental Well-being and Financial Well-being domain scores (each PB < 0.05). Ethnicity was associated with the SCQOLS-15 Physical Well-being and Experience & Meaning domains (each PB < 0.05). The percentiles for the short forms showed moderate to substantial agreement with those for the full-length version in terms of classifying caregivers into percentile intervals (quadratic-weighted Kappa = 0.72 to 0.92).ConclusionReference values for the SCQOLS-15 and SCQOLS-10 were estimated in relation to caregiver characteristics to facilitate interpretation of the short form scores.

Evaluation of APOE polymorphisms and the risk for age-related macular degeneration in a Southeastern Brazilian population.

This study aimed to evaluate the role of APOE polymorphisms (rs429358 and rs7412) in the risk of age-related macular degeneration in a sample of the Southeastern Brazilian population. Seven hundred and five unrelated individuals were analyzed, 334 with age-related macular degeneration (case group), and 371 without the disease (control group). In the case group, patients were further stratified according to disease phenotypes, divided into dry and wet age-related macular degeneration, and non-advanced and advanced age-related macular degeneration. APOE polymorphisms (rs429358 and rs7412) were evaluated through polymerase chain reaction and direct sequencing. In the comparison of cases vs. controls, none of the associations reached statistical significance, considering the Bonferroni-adjusted P-value, although there was a suggestive protection for the E3/E4 genotype (OR = 0.626; P-value = 0.037) and E4 carriers (OR = 0.6515; P-value = 0.047). Statistically significant protection for both the E3/E4 genotype and E4 carriers was observed in the comparisons: advanced age-related macular degeneration vs. controls (OR = 0.3665, P-value = 0.491 × 10-3 and OR = 0.4031, P-value = 0.814 × 10-3, respectively), advanced age-related macular degeneration vs. non-advanced age-related macular degeneration (OR = 0.2529, P-value = 0.659 × 10-4 and OR = 0.2692, P-value = 0.631 × 10-4, respectively). In the comparison of wet age-related macular degeneration vs. control, protection was statistically significant only for E3/E4 (OR = 0.4052, P-value = 0.001). None of the comparisons demonstrated any significant association for E2 genotypes or E2 carriers in age-related macular degeneration risk in this study. Findings suggest a protective role of the E4 haplotype in the APOE gene in the risk for advanced and wet forms of age-related macular degeneration, in a sample of the Brazilian population. To our knowledge, this is the first Brazilian study to show the association between APOE polymorphisms and age-related macular degeneration.

DNA Copy Number Variation Associated with Anti-tumour Necrosis Factor Drug Response and Paradoxical Psoriasiform Reactions in Patients with Moderate-to-severe Psoriasis.

Biological drugs targeting tumour necrosis factor are effective for psoriasis. However, 30–50% of patients do not respond to these drugs and may even develop paradoxical psoriasiform reactions. This study searched for DNA copy number variations that could predict anti-tumour necrotic factor drug response or the appearance of antitumour necrotic factor induced psoriasiform reactions. Peripheral blood samples were collected from 70 patients with anti-tumour necrotic factor drug-treated moderate-to-severe plaque psoriasis. Samples were analysed with an Illumina 450K methylation microarray. Copy number variations were obtained from raw methylation data using conumee and Chip Analysis Methylation Pipeline (ChAMP) R packages. One copy number variation was found, harbouring one gene (CPM) that was significantly associated with adalimumab response (Bonferroni-adjusted p-value < 0.05). Moreover, one copy number variation was identified harbouring 3 genes (ARNT2, LOC101929586 and MIR5572) related to the development of paradoxical psoriasiform reactions. In conclusion, this study has identified DNA copy number variations that could be good candidate markers to predict response to adalimumab and the development of anti-tumour necrotic factor paradoxical psoriasiform reactions.

Metabolomic signatures of cardiac remodelling and heart failure risk in the community.

AimsHeart failure (HF) is associated with several metabolic changes, but it is unknown whether distinct components of the circulating metabolome may be related to cardiac structure and function, and with incident HF in the community.Methods and resultsWe assayed 217 circulating metabolites in 2336 Framingham Study participants (mean age 55 ± 10 years, 53% women) without HF at baseline. We used linear and Cox regression to relate concentrations of metabolites to left ventricular (LV) diastolic dimension, LV wall thickness, LV ejection fraction, left atrial dimension, LV ventricular mass, and aortic root size cross‐sectionally and to incident HF prospectively. Bonferroni‐adjusted P‐values <0.05 denoted statistical significance. Circulating concentrations of kynurenine [β = −0.12 cm per standard deviation (SD) increment in normalized residual of metabolite, P = 7.3 × 10−8] and aminoadipate (−0.11 cm per SD increment, P = 2.61 × 10−5) were associated with left ventricular diastolic dimension, phosphatidylcholine (carbon:double bound = 38:6) with left atrial dimension (0.10 cm per SD increment, P = 9.7 × 10−6), and cholesterol ester (carbon:double bound = 20:5) with left atrial dimension (0.10 cm per SD increment, P = 1.4 × 10−5) in multivariable‐adjusted models. During an average follow‐up of 15.8 (range 0.02–23.2) years, 113 participants (5%) were diagnosed with HF with reduced ejection fraction and 106 individuals (5%) with HF with preserved ejection fraction. In multivariable analyses, concentrations of phosphatidylcholine (hazard ratio 0.63, P = 1.3 × 10−5) and ornithine (hazard ratio 1.44, P = 0.00014) were associated with HF with reduced ejection fraction.ConclusionsSeveral metabolites, including the vasoactive metabolite kynurenine, were related to cardiac structure and function in our sample. Additional research is warranted to confirm our observations and investigate if these metabolites can risk stratify ambulatory individuals.

Quantifying Impact of Disruption to Radiology Education During the COVID-19 Pandemic and Implications for Future Training

PurposeThe aim of this study was to assess the impact on radiology resident education due to the COVID-19 pandemic in order to inform future educational planning. MethodsDuring a 10-week study period from March 16 to May 22, 2020, changes to educational block-weeks (BW) of first through fourth year residents (R1-4) were documented as disrupted in the setting of the COVID-19 pandemic. The first 5 weeks and the second 5 weeks were evaluated separately for temporal differences. Overall and mean disrupted BW per resident were documented. Wilcoxon rank-sum tests were used to assess pairwise differences between classes with Bonferroni-adjusted P-values, as well as differences in the early versus later phase of the pandemic. ResultsOf 373 BW, 56.6% were assigned to virtual curriculum, 39.4% radiology clinical duties, 2.9% illness, and 1.1% reassignment. Scheduling intervention affected 6.2 ± 2.3 (range 1-10) mean BW per resident over the 10-week study period. The R3 class experienced the largest disruption, greater than the R2 classes, and statistically significantly more than the R1 and R4 classes (both P < 0.05). The second half of the pandemic caused statistically significantly more schedule disruptions than the first half (P = 0.009). DiscussionThe impact of COVID-19 pandemic varied by residency class year, with the largest disruption of the R3 class and the least disruption of the R4 class. To optimize future educational opportunities, shifting to a competency-based education paradigm may help to achieve proficiency without extending the length of the training program.

Genome-Wide Association Study of Weaning Traits in Lori-Bakhtiari Sheep

Abstract Weaning traits, including preweaning daily gain (PWDG) and weaning weight (WW) are important economic traits, especially for meat type mammals, with high impacts on growth performance and survival rate in higher ages. This study was conducted to perform a genome-wide association study (GWAS) on weaning traits in a meat type breed of sheep. Body weight records of 7557 Lori-Bakhtiari sheep with PWDG and WW records were used to estimate breeding values (EBVs) using an animal mixed model. A total of 132 animals were selected by two-tailed selection strategy, based on EBVs for body weight and then were genotyped using Illumina 50k Ovine SNP chip. After quality control, a total of 130 animals and 41323 SNPs were remained for further analyses. De-regressed estimates of breeding values were used as a pseudo-phenotype in GWAS analysis. Based on Bonferroni-adjusted p-values, five SNPs, located on chromosomes 2, 3, 4, 12 and 22 were significantly (p &lt; 0.05) associated with weaning traits and accounted for 5.06% and 0.37% of total genetic variations of PWDG and WW, respectively. Two SNPs on chromosomes 2 and 3 were located near to previously reported QTLs for weaning traits. Three genes, including ANGPTL7, mTOR and WDR11, were found within 50 kbp distances from the significant SNPs and thus could be considered as candidate genes for weaning traits. The detected QTLs and candidate genes could be studied for construction of breeding programs for genetic improvement of growth performance in meat type sheep.

Tu1046 EFFECT OF AN EDUCATIONAL POLYPECTOMY WORKSHOP ON CHOICE OF TOOL UTILIZED BY GENERAL ENDOSCOPIST DURING COLONOSCOPY

Optimal removal of diminutive (<5mm) polyps (DP) has been evaluated in multiple studies. Studies have compared and shown that polyp removal via cold snare polypectomy (CSP) is superior to removal via jumbo biopsy forceps (JBF), especially for DP measuring 4-5mm. Despite this, many general endoscopists still utilize JBF as the standard approach for DP removal. Our study sought to determine if a polypectomy educational session would increase the rate of CSP among general endoscopists. General endoscopists at a tertiary care center underwent an educational session discussing the optimal methods of polyp removal, followed by a hands-on laboratory session. Participants underwent surveys analyzing comfort regarding removal of polyps before and immediately after the session. Changes in polypectomy practice was analyzed by looking at random 2 week intervals of all colonoscopies performed by general endoscopists prior to, immediately after, and 6 months after the educational session was completed. Endoscopy notes were retroactively analyzed to gather data on number of polyps removed, polyp size, method of removal, and patient characteristics. Chi Square analysis was utilized to compare the change in polypectomy method across the three time points. 17 general endoscopists underwent the education session. Surveyed participants experienced a small subjective improvement in comfort using CS for removal of polyps and with removal of flat polyps less than 10mm. 218 colonoscopy patients (54.9% female) were evaluated before (n=97), immediately after (n=83), and 6 months after (n=88) the polypectomy seminar. There was no significant difference between age, BMI, prep quality, and polyp size amongst groups. There was a significant increase in CS compared to JBF use for the removal of ≥ 4mm polyps immediately after the session (p=0.0008 using Bonferroni-adjusted p-value). There was an insignificant decline in the proportion of CS use at 6 months post intervention compared to immediately-after the workshop (p=0.108). When broken down further, the proportion of 4mm polyps removed with a CS rather than JBF significantly increased immediately after the educational session and was sustained at 6 months post intervention (p=0.0004). There was no significant change in rates of CS use for 5mm polyps, although data showed it was used >90% of the time prior to the educational intervention (p=0.1420). An educational session with didactic and hands-on components appears to be an effective way to increase proportion of CS use for DP removal at a tertiary care center, thereby likely improving resection margins. Further studies will evaluate if these results remain sustained and if this session would be of benefit to endoscopists in a community setting.Proportion of cold snare compared to jumbo biopsy forceps utilization in polypectomy for polyps 4-5mm in size.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

S4. IDENTIFYING HETEROGENEITY IN SYMPTOM NETWORKS IN THE GENERAL POPULATION: A RECURSIVE PARTITIONING APPROACH

BackgroundNetwork models of psychopathology have gained increasing ground recently. It is suggested that psychopathology arises from the reciprocal associations between symptoms and other psycho-biological factors. Given the heterogeneity in psychopathological phenomena, it seems likely that subgroups with distinct network structures may emerge given different demographic and environmental risk factors. Thus, the identification of heterogeneity in symptom networks associated with specific variables may promote an understanding of the mechanisms that underlie the relation between environmental factors and psychopathology.MethodsWe took a recursive partitioning approach based on conditional inference trees that iteratively splits the sample of interest based on a predefined set of covariates to detect subgroups with significantly different network structures, resulting in a network tree. We used general population data from the 2000 and 2007 English National Survey of Psychiatric Morbidity, with a combined sample size of n = 15,983 (age range: 16–95 years, 55.9% female), to model networks of psychotic experiences (hallucinations, persecutory ideation) and affective symptoms (worry, mood instability, depression, anxiety, sleep problems). Split variables explored as sources of heterogeneity in networks were sex, age, and exposure to environmental risk factors (cannabis use in past month, lifetime sexual abuse, lifetime experience of bullying). We used a stop-splitting rule based on Bonferroni-adjusted p-values to determine the final tree size (α = .01).ResultsEnvironmental factors were the primary sources of heterogeneity in network structures, with exposure to these factors being linked to more densely connected networks. Globally, cannabis use was associated with particularly strong connections between hallucinations and persecutory ideation, depression and persecutory ideation, and depression and mood instability. In those participants with cannabis use and experiences of sexual abuse, the association between depression and persecutory ideation was particularly strong, and further, strong connections were present between the affective symptoms. Similarly, those with exposure to both cannabis and bullying showed stronger associations involving sleep problems than participants exposed to either bullying or cannabis alone. Exposure to either bullying or sexual abuse without concurrent cannabis use was linked to a strongly connected cluster of worry, anxiety, and depression, with only weak associations to other symptoms. Lastly, the sample was split at 60 years of age. The younger group was divided further by age, with participants younger than 26 years showing stronger associations between hallucinations and persecutory ideation and worry and depression than those older than 26 years. In participants older than 60 years, another split was made by gender: women showed a more densely connected network than men.DiscussionFindings from this exploratory analysis document substantial heterogeneity in symptom network structures in a large general population sample. Exposure to risk factors is linked to more strongly connected, probably less resilient symptom networks, with evidence for additive vulnerability given the presence of several risk factors. Exposure to sexual abuse or bullying mainly seems to relate to higher connectivity of affective symptoms, while cannabis use links to higher connection of psychotic symptoms with each other, but also with affective symptoms. The analysis also highlights demographic variables as sources of heterogeneity in symptom networks, pointing to specifically relevant symptom interactions in subgroups of age and gender.

Effect of chronic exercise in healthy young male adults: a metabolomic analysis.

To examine the metabolic adaptation to an 80-day exercise intervention in healthy young male adults where lifestyle factors such as diet, sleep, and physical activities are controlled. This study involved cross-sectional analysis before and after an 80-day aerobic and strength exercise intervention in 52 young, adult, male, newly enlisted soldiers in 2015. Plasma metabolomic analyses were performed using liquid chromatography, tandem mass spectrometry. Data analyses were performed between March and August 2019. We analysed changes in metabolomic profiles at the end of an 80-day exercise intervention compared to baseline, and the association of metabolite changes with changes in clinical parameters. Global metabolism was dramatically shifted after the exercise training programme. Fatty acids and ketone body substrates, key fuels used by exercising muscle, were dramatically decreased in plasma in response to increased aerobic fitness. There were highly significant changes across many classes of metabolic substrates including lipids, ketone bodies, arginine metabolites, endocannabinoids, nucleotides, markers of proteolysis, products of fatty acid oxidation, microbiome-derived metabolites, markers of redox stress, and substrates of coagulation. For statistical analyses, a paired t-test was used and Bonferroni-adjusted P-value of <0.0004 was considered to be statistically significant. The metabolite dimethylguanidino valeric acid (DMGV) (recently shown to predict lack of metabolic response to exercise) tracked maladaptive metabolic changes to exercise; those with increases in DMGV levels had increases in several cardiovascular risk factors; changes in DMGV levels were significantly positively correlated with increases in body fat (P = 0.049), total and LDL cholesterol (P = 0.003 and P = 0.007), and systolic blood pressure (P = 0.006). This study was approved by the Departments of Defence and Veterans' Affairs Human Research Ethics Committee and written informed consent was obtained from each subject. For the first time, the true magnitude and extent of metabolic adaptation to chronic exercise training are revealed in this carefully designed study, which can be leveraged for novel therapeutic strategies in cardiometabolic disease. Extending the recent report of DMGV's predictive utility in sedentary, overweight individuals, we found that it is also a useful marker of poor metabolic response to exercise in young, healthy, fit males.

A computational method to quantitatively measure pediatric drug safety using electronic medical records

BackgroundDrug safety in children is a major concern; however, there is still a lack of methods for quantitatively measuring, let alone to improving, drug safety in children under different clinical conditions. To assess pediatric drug safety under different clinical conditions, a computational method based on Electronic Medical Record (EMR) datasets was proposed.MethodsIn this study, a computational method was designed to extract the significant drug-diagnosis associations (based on a Bonferroni-adjusted hypergeometric P-value < 0.05) among drug and diagnosis co-occurrence in EMR datasets. This allows for differences between pediatric and adult drug use to be compared based on different EMR datasets. The drug-diagnosis associations were further used to generate drug clusters under specific clinical conditions using unsupervised clustering. A 5-layer quantitative pediatric drug safety level was proposed based on the drug safety statement of the pediatric labeling of each drug. Therefore, the drug safety levels under different pediatric clinical conditions were calculated. Two EMR datasets from a 1900-bed children’s hospital and a 2000-bed general hospital were used to test this method.ResultsThe comparison between the children’s hospital and the general hospital showed unique features of pediatric drug use and identified the drug treatment gap between children and adults. In total, 591 drugs were used in the children’s hospital; 18 drug clusters that were associated with certain clinical conditions were generated based on our method; and the quantitative drug safety levels of each drug cluster (under different clinical conditions) were calculated, analyzed, and visualized.ConclusionWith this method, quantitative drug safety levels under certain clinical conditions in pediatric patients can be evaluated and compared. If there are longitudinal data, improvements can also be measured. This method has the potential to be used in many population-level, health data-based drug safety studies.

Genetically Determined Physical Activity and Its Association with Circulating Blood Cells.

Lower levels of physical activity (PA) have been associated with increased risk of cardiovascular disease. Worldwide, there is a shift towards a lifestyle with less PA, posing a serious threat to public health. One of the suggested mechanisms behind the association between PA and disease development is through systemic inflammation, in which circulating blood cells play a pivotal role. In this study we investigated the relationship between genetically determined PA and circulating blood cells. We used 68 single nucleotide polymorphisms associated with objectively measured PA levels to perform a Mendelian randomization analysis on circulating blood cells in 222,645 participants of the UK Biobank. For inverse variance fixed effects Mendelian randomization analyses, p < 1.85 × 10−3 (Bonferroni-adjusted p-value of 0.05/27 tests) was considered statistically significant. Genetically determined increased PA was associated with decreased lymphocytes (β = –0.03, SE = 0.008, p = 1.35 × 10−3) and decreased eosinophils (β = –0.008, SE = 0.002, p = 1.36 × 10−3). Although further mechanistic studies are warranted, these findings suggest increased physical activity is associated with an improved inflammatory state with fewer lymphocytes and eosinophils.

Associations between PM2.5 and mid-pregnancy inflammation measured using a novel proteomics chip

OPS 20: Chemicals, biomarkers, omics, Room 110, Floor 1, August 27, 2019, 4:30 PM - 5:30 PM Background/Aim: Prenatal fine particulate matter (PM2.5) exposure is linked with adverse pregnancy outcomes and developmental problems in children; PM2.5-induced changes to maternal immune activity may underlie these relationships. We examined maternal prenatal PM2.5 exposure in relation to inflammatory signals using a targeted proteomics approach. Methods: Analyses include 373 pregnant women enrolled in a prospective study in the northeastern United States between 2011 and 2015. We estimated daily residential PM2.5 exposure using high-resolution satellite data combined with ground monitoring measures and spatiotemporal predictors. We analyzed 92 inflammatory proteins in mid-pregnancy serum using a novel multiplex proximity extension assay. To explore the influence of exposure timing, we examined PM2.5 averaged across the previous 3 months, 1 month, or week of blood draw. We regressed PM2.5 on each inflammatory marker in separate models adjusting for week of gestation, maternal age, and season. For associations with a Bonferroni-adjusted p-value <0.05, we next used multivariable logistic regression to examine continuous PM2.5 exposure in relation to high (highest 20%) versus low (lowest 80%) inflammatory marker levels. Results: Mothers were primarily minorities (60% black or Hispanic). After Bonferroni correction, monocyte-chemotactic protein-3 (MCP-3), interleukin-8 (IL-8), and oncostatin M (OSM) were (p<0.001) positively associated with PM2.5 for one or more exposure interval. The odds of having high MCP-3 levels increased per unit (µg/m3) increase in PM2.5 when averaged across the previous 3 months (OR=1.48, 95% CI=1.22, 1.80), 1 month (OR=1.30, 95%CI=1.12, 1.51), or week (OR=1.18, 95% CI=1.06, 1.31). Parallel findings were true for OSM (1 month: OR=1.24, 95% CI=1.08, 1.44; 1 week: OR=1.22, 95% CI=1.10, 1.35) and IL-8 (1 month: OR=1.27, 95% CI=1.10, 1.46; 1 week: OR=1.23, 95% CI=1.11, 1.37) for more recent exposure only. Conclusions: These data link increased prenatal PM2.5 with markers of enhanced inflammation. Future analysis in this longitudinal cohort will examine whether identified markers (MCP3, OSM and IL8) mediate associations between PM2.5 and maternal-child health outcomes.

Discovery of potential urine-accessible metabolite biomarkers associated with muscle disease and corticosteroid response in the mdx mouse model for Duchenne.

Urine is increasingly being considered as a source of biomarker development in Duchenne Muscular Dystrophy (DMD), a severe, life-limiting disorder that affects approximately 1 in 4500 boys. In this study, we considered the mdx mice—a murine model of DMD—to discover biomarkers of disease, as well as pharmacodynamic biomarkers responsive to prednisolone, a corticosteroid commonly used to treat DMD. Longitudinal urine samples were analyzed from male age-matched mdx and wild-type mice randomized to prednisolone or vehicle control via liquid chromatography tandem mass spectrometry. A large number of metabolites (869 out of 6,334) were found to be significantly different between mdx and wild-type mice at baseline (Bonferroni-adjusted p-value < 0.05), thus being associated with disease status. These included a metabolite with m/z = 357 and creatine, which were also reported in a previous human study looking at serum. Novel observations in this study included peaks identified as biliverdin and hypusine. These four metabolites were significantly higher at baseline in the urine of mdx mice compared to wild-type, and significantly changed their levels over time after baseline. Creatine and biliverdin levels were also different between treated and control groups, but for creatine this may have been driven by an imbalance at baseline. In conclusion, our study reports a number of biomarkers, both known and novel, which may be related to either the mechanisms of muscle injury in DMD or prednisolone treatment.