Statistical Interaction Research Articles

Network analysis of synovial RNA sequencing identifies gene-gene interactions predictive of response in rheumatoid arthritis

BackgroundTo determine whether gene-gene interaction network analysis of RNA sequencing (RNA-Seq) of synovial biopsies in early rheumatoid arthritis (RA) can inform our understanding of RA pathogenesis and yield improved treatment response prediction models.MethodsWe utilized four well curated pathway repositories obtaining 10,537 experimentally evaluated gene-gene interactions. We extracted specific gene-gene interaction networks in synovial RNA-Seq to characterize histologically defined pathotypes in early RA and leverage these synovial specific gene-gene networks to predict response to methotrexate-based disease-modifying anti-rheumatic drug (DMARD) therapy in the Pathobiology of Early Arthritis Cohort (PEAC). Differential interactions identified within each network were statistically evaluated through robust linear regression models. Ability to predict response to DMARD treatment was evaluated by receiver operating characteristic (ROC) curve analysis.ResultsAnalysis comparing different histological pathotypes showed a coherent molecular signature matching the histological changes and highlighting novel pathotype-specific gene interactions and mechanisms. Analysis of responders vs non-responders revealed higher expression of apoptosis regulating gene-gene interactions in patients with good response to conventional synthetic DMARD. Detailed analysis of interactions between pairs of network-linked genes identified the SOCS2/STAT2 ratio as predictive of treatment success, improving ROC area under curve (AUC) from 0.62 to 0.78. We identified a key role for angiogenesis, observing significant statistical interactions between NOS3 (eNOS) and both CAMK1 and eNOS activator AKT3 when comparing responders and non-responders. The ratio of CAMKD2/NOS3 enhanced a prediction model of response improving ROC AUC from 0.63 to 0.73.ConclusionsWe demonstrate a novel, powerful method which harnesses gene interaction networks for leveraging biologically relevant gene-gene interactions leading to improved models for predicting treatment response.

Associations of Two Common Polymorphisms in MTHFR Gene with Blood Lipids and Therapeutic Efficacy of Simvastatin.

Cardio-cerebrovascular disease is an important public health challenge worldwide, and its complex etiology has not been elucidated fully. The study investigated the relationship between two common polymorphisms, C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, baseline lipids and the lipid-lowering efficacy of simvastatin in a Chinese hyperlipidemic population. All participants were recruited from Anhui, China. By the extreme sampling method, we selected subjects with a low response (n=108) and high response (n=106) based on their adjusted lipid-lowering response to simvastatin administrated for 8 consecutive weeks. Both MTHFR C677T and A1298C loci were genotyped by the MALDI-TOF MS platform. Serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were measured at baseline and after 8 weeks of oral 20 mg/d tablets of simvastatin. Patients with the 677TT genotype had significantly higher baseline TC, HDL-C, and change in HDL-C (ΔHDL-C) levels after treatment than those with 677CC+CT genotypes (β = 0.207, P = 0.045; β = 0.182, P = 0.026; and β = 0.16, P = 0.002, respectively). Patients with 1298AC+CC genotypes had significantly higher baseline LDL-C and change in LDL-C (ΔLDL-C) levels (β = 0.276, P =0.043; β = 0.359, P = 0.025, respectively) than those with 1298AA genotype. We found statistical interactions between the two SNPs in association with baseline HDL-C (P for interaction = 0.034), TC (P for interaction = 0.069), and TG (P for interaction = 0.034). Baseline TC (P = 0.027) and HDL-C (P = 0.046) and change in HDL-C (P = 0.019) were different among those with the MTHFR A-T haplotype compared with A-C. Our major findings suggest that both MTHFR C677T and A1298C polymorphisms could be important genetic determinants of lipid traits and drug efficacy of simvastatin. This will contribute to a better understanding of strategies for personalized medication in Chinese patients with dyslipidemia.

The Association between Hypertriglyceridemia and Colorectal Cancer: A Long-Term Community Cohort Study in Taiwan.

(1) Background: Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer deaths worldwide. It often diagnosed at advanced stages, and with increasing incidence at younger generation. CRC poses a heavy financial burden and a huge public health challenge nowadays. Lipoproteins and serum lipids may have an influence on carcinogenesis by making oxidative stress, inflammation, and insulin resistance. Dyslipidemia plays a potential role in the risk of CRC. The purpose of this study is to use nationally representative samples to determine epidemiologic characteristics of CRC in the Taiwanese population, and to evaluate the associations between baseline levels of lipid profile and their effect on risk of colorectal cancer (CRC) comprehensively and quantitatively. The control of dyslipidemia in primary and secondary prevention may reduce the disease burden of CRC. (2) Methods: This is a nationwide long-term community-based prospective cohort study. Data were retrieved from the nationwide population-based Taiwanese Survey on Hypertension, Hyperglycemia and Hyperlipidemia (TwSHHH). Variables were estimated by the Cox proportional hazards model which was then further adjusted for age. We also calculated the relative ratios (RRs) of CRC for joint categories of serum cholesterol, triglyceride (TG), low-density lipoproteins cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) level, and to examine their combined effect and statistical interactions. (3) Results: Male, age, waist circumference, diabetes mellitus (DM), high TG, high cholesterol level, smoking history, and metabolic syndrome were proved to increase the risk of CRC. In addition, DM patients with a TG level ≥150 mg/dL and cholesterol ≥180 mg/dL had a 4.118-fold higher risk of CRC as compared with a TG level <150 mg/dL and cholesterol level <180 mg/dL, which was a significant difference (95% CI, 1.061–15.975; p = 0.0407). (4) Conclusions: Patients with DM should control TG and cholesterol level through diet, exercise, or taking medications more aggressively, not only for preventing cardiovascular disease, but also for first prevention of CRC. The study can be valuable for the clinicians and policy makers to implement more precisely goals about dyslipidemia management.

Human leukocyte antigen-haploidentical transplantation for relapsed/refractory acute myeloid leukemia: Better leukemia-free survival with bone marrow than with peripheral blood stem cells in patients ≥55 years of age.

The best stem cell source for T-cell replete human leukocyte antigen (HLA)-haploidentical transplantation with post-transplant cyclophosphamide (PTCy) remains to be determined. In this European Society for Blood and Marrow Transplantation retrospective study, we analyzed the impact of stem cell source on leukemia-free survival (LFS) in adult patients with primary refractory or relapsed acute myeloid leukemia (AML) given grafts from HLA-haploidentical donors with PTCy as graft-versus-host disease (GVHD) prophylaxis. A total of 668 patients (249 bone marrow [BM] and 419 peripheral blood stem cells [PBSC] recipients) met the inclusion criteria. The use of PBSC was associated with a higher incidence of grade II-IV (HR=1.59, p=.029) and grade III-IV (HR=2.08, p=.013) acute GVHD. There was a statistical interaction between patient age and the impact of stem cell source for LFS (p < .01). In multivariate Cox models, among patients <55 years, the use of PBSC versus BM resulted in comparable LFS (HR=0.82, p=.2). In contrast, in patients ≥55 years of age, the use of PBSC versus BM was associated with higher non-relapse mortality (NRM) (HR=1.7, p=.01), lower LFS (HR=1.37, p=.026) and lower overall survival (HR=1.33, p=.044). In conclusions, our data suggest that in patients ≥55 years of age with active AML at HLA-haploidentical transplantation, the use of BM instead of PBSC as stem cell source results in lower NRM and better LFS. In contrast among younger patients, the use of PBSC results in at least a comparable LFS.

Combined Association of Low-Density Lipoprotein Cholesterol Levels and Systolic Blood Pressure to the Outcome of Intracerebral Hemorrhage: Data from the China Stroke Center Alliance.

Limited data were available about the combined impact of systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) levels on intracerebral hemorrhage (ICH) prognosis. The objective of this study is to explore whether the relationship between LDL-C and ICH outcomes was modified by SBP levels in a Chinese population. From August 1, 2015, to July 31, 2019, 75,443 ICH patients enrolled from the Chinese Stroke Center Alliance program were included in our study. Patients were divided into LDL-C levels of <70 mg/dL, 70-100 mg/dL, and ≥100 mmol/L. SBP was stratified as <140 mmHg, 140-180 mmHg, and ≥180 mmHg. The primary outcome was the occurrence of hematoma expansion (HE), and the second outcome was in-hospital mortality. Correlation between LDL-C levels and SBP on ICH outcomes were assessed by logistic regression. 6,116 (8.1%) and 1,576 (2.1%) patients suffered HE and in-hospital mortality. Compared with the ≥100 mg/dL group, patients with LDL-C concentrations under 70 mg/dL had a 19% and 24% increase in the relative risk of HE (crude OR 1.19, 95% CI 1.11-1.28) and in-hospital mortality (crude OR 1.24, 95% CI 1.08-1.42). When SBP was added as a stratification variable, the above-mentioned association was attenuated in patients under a threshold SBP of 140 mmHg (P > 0.05). However, no statistical interaction was detected between SBP and LDL-C levels. Lower LDL-C levels (<70 mg/dL) are related to a higher risk of HE and in-hospital mortality confined to ICH patients with elevated SBP (≥140 mmHg).

Abstract 5937: Are female cancer survivors meeting exercise recommendations for cancer survivorship: Evaluation of disparities by race/ethnicity and US nativity

Abstract Purpose: We examined disparities among female cancer survivors in associations between race/ethnicity, United Statues (US) nativity, and odds of meeting the American College of Sports Medicine (ACSM) weekly exercise recommendations for adult cancer survivors, determining if different by comorbidity and obesity status. Methods: We analyzed 2,044 adult females with a history of cancer 2+ years since initial cancer diagnosis from the National Health and Nutrition Examination Survey (NHANES 1999-2018). Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression for associations between race/ethnicity (non-Hispanic white [NHW], non-Hispanic Black [NHB], Hispanic/Mexican American, additional racial/ethnic groups), US nativity (US-born, foreign-born), and time of acculturation (US-born, foreign-born &amp;lt;15 years in US, foreign-born ≥15 years in US) and odds of meeting weekly exercise recommendations accounting for examination weights and covariates. Statistical interactions between stratifications (comorbidity status [none, at least one]; BMI [underweight/normal, overweight/obese]) were conducted. Results: Most were breast cancer survivors (33.8%), NHW (64.1%), born in the US (84.5%), overweight/obese (69.9%), and did not meet recommendations (66.5%). NHB survivors were significantly less likely to meet recommendations (aOR, 0.66, 95% CI, 0.47-0.92) than NHW survivors. Foreign-born women were 3.41 times more likely to meet recommendations (95% CI, 1.18-9.85) compared to US-born women. Survivors who were foreign-born and lived in the US for ≥15 years were significantly less likely to meet recommendations (aOR, 0.43, 95% CI, 0.21-0.87) compared to US natives. Comorbidity status significantly modified (p-interaction&amp;lt; 0.05) the associations between US nativity and time of acculturation and BMI modified the relationship between race/ethnicity and odds of meeting recommendations (p-interaction=0.013). NHB survivors who were underweight/normal weight were 2 times more likely (95% CI, 0.96-4.77) to meet recommendations while overweight/obese NHB survivors were significantly less likely (aOR, 0.27; 95% CI 0.13-0.56). Conclusion: Our study results confirm that racial/ethnic disparities exist in meeting exercise recommendations among NHB survivors, particularly those overweight/obese. Our findings provide new evidence for disparities in meeting exercise recommendations among female cancer survivors born outside of the US. While foreign-born survivors were more likely to meet recommendations, living in the US for 15+ years was significantly associated with reduced odds of meeting recommendations. Results can inform researchers and clinicians to better tailor lifestyle and exercise interventions for these women to identify barriers for improving adherence. Citation Format: Kate E. Dibble, Avonne E. Connor. Are female cancer survivors meeting exercise recommendations for cancer survivorship: Evaluation of disparities by race/ethnicity and US nativity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5937.

Abstract LB554: Multimorbidity and healthy lifestyle behaviors among US-based female cancer survivors

Abstract Purpose: The current study examined the associations between multimorbidity and odds of maintaining healthy lifestyle behaviors (meeting the American College of Sports Medicine weekly physical activity (PA) recommendations for adults, daily alcohol consumption, and smoking history) among adult female cancer survivors and examined differences by age at cancer diagnosis and race/ethnicity. Methods: 2,005 adult females with a history of cancer two or more years since initial cancer diagnosis from the National Health and Nutrition Examination Survey (1999-2018) were included. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression for the associations between multimorbidity (≥2 comorbid conditions) and health behaviors, accounting for survey examination weights and covariates. Models were stratified by age at diagnosis and race/ethnicity and statistical interactions were examined to evaluate effect modification. Results: Overall, female cancer survivors with multimorbidity were more likely to be ever smokers (aOR, 1.42; 95% CI 1.08-1.85) and were significantly less likely to drink ≥2 alcoholic drinks/day (aOR, 0.67; 95% CI 0.50-0.91) in comparison to female survivors without multimorbidity. This association with alcohol was significantly modified by race/ethnicity (non-Hispanic white (NHW) survivors: aOR, 0.61; 95% CI 0.44-0.86; minority survivors aOR, 1.09; 95% CI 0.67-1.79; p-interaction=0.04) and age at diagnosis (≥50 years of age at diagnosis: aOR, 0.44; 95% CI 0.28-0.69; &amp;lt;50 years at diagnosis: aOR, 0.88; 95% 0.59-1.31; p-interaction=0.03). Overall, the association between multimorbidity and PA was not statistically significant. However, by race/ethnicity, minority cancer survivors with multimorbidity were two times more likely to meet weekly PA recommendations (aOR, 2.10; 95% CI 1.29-3.41), in comparison with minority survivors without multimorbidity; and there was no association observed among NHW survivors (p-interaction=0.005). By age at diagnosis, women ≥50 years with multimorbidity were also more likely to meet PA recommendations (aOR, 1.65: 95% CI 1.04-2.62) while women &amp;lt;50 years were less likely to meet PA recommendations (p-interaction=0.02). Conclusions: Our findings indicate that female cancer survivors with multimorbidity are more likely to be ever smokers and less likely to drink ≥2 alcoholic drinks/day. The associations between multimorbidity, alcohol consumption, and meeting PA recommendations significantly differed by race/ethnicity and age at cancer diagnosis. Identification of at risk groups of female cancer survivors with multimorbidity can help inform more targeted behavioral intervention studies among these women who are at increased risk of poor outcomes due to their chronic health conditions and cancer history. Citation Format: Avonne E. Connor, Kate E. Dibble. Multimorbidity and healthy lifestyle behaviors among US-based female cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB554.

Abstract LB158: Total, LDL-, HDL-cholesterol, apolipoproteins, and triglycerides and risk fatal prostate cancer in black and white men in the ARIC study

Abstract Background: Cholesterol reduction is considered a mechanism through which lipid-lowering drugs including statins are associated with a reduced aggressive prostate cancer risk. While prior cohort studies found positive associations of total cholesterol with advanced stage and grade in White men based mostly on cholesterol at baseline, whether associations for total cholesterol, low (LDL)- and high (HDL)-density lipoprotein cholesterol, apolipoprotein B (LDL particle component) and A1 (HDL particle component), and triglycerides exist for fatal prostate cancer and in Black men using time-updated biomarkers is unknown. Methods: We conducted a prospective study of 1,553 Black and 5,071 White cancer-free men attending visit 1 (1987-1989) of the Atherosclerosis Risk in Communities Study. Death from prostate cancer was ascertained from the underlying cause on death certificates. Follow-up began at visit 1 and ended at date of death, loss to follow-up, or 12/31/2018, which ever came first. There were 128 deaths from prostate cancer (43 in Black men, 85 in White men) ascertained over 153,184 person years of follow-up (mean 23 years). We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for fatal prostate cancer per 1-standard deviation increment and for tertiles (T1-T3) of time-updated lipid biomarkers adjusting for baseline age, education, race and field center, and updated BMI, waist circumference, smoking status, hyperglycemia and diagnosed diabetes, aspirin use, and lipid-lowering drug use overall, and in Black and White men. Results: Higher total cholesterol concentration was associated with higher fatal prostate cancer risk in White men only (HR per-1 SD=1.25; 95%CI=1.00-1.58), and higher concentration of LDL cholesterol appeared to be associated with fatal prostate cancer in White men only (HR per-1 SD=1.26; 95%CI=0.99-1.60). Apolipoprotein B was non-linearly associated with fatal prostate cancer overall (T2 vs. T1 HR=1.66; 95% CI=1.05-2.64) and in Black men (T2 vs. T1 HR=3.59; 95% CI=1.53-8.40) but not in White men (T2 vs. T1 HR=1.13; 95% CI=0.65-1.97). HRs were &amp;gt;1 overall (T3 vs. T1 HR=1.18) and in Black men (T3 vs. T1 HR=2.11) but were not statistically significant. HDL-cholesterol, Apolipoprotein A1 and triglycerides were not associated with fatal prostate cancer overall and by race. Tests for statistical interaction by race were not statistically significant. Conclusion: Positive associations with fatal prostate cancer were observed with total and LDL-cholesterol in White men, and apolipoprotein B in Black men. These findings may improve the understanding of lipid metabolism in prostate carcinogenesis, and further emphasize the importance of cholesterol control. Support: NHLBI contracts, NCI grants, NPCR Citation Format: Michael T. Marrone, Anna E. Prizment, David Couper, Kenneth R. Butler, Brad C. Astor, Corinne E. Joshu, Elizabeth A. Platz, Alison M. Mondul. Total, LDL-, HDL-cholesterol, apolipoproteins, and triglycerides and risk fatal prostate cancer in black and white men in the ARIC study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB158.

Direct and indirect plant-soil interactions in a semi-arid Mediterranean shrubland (NE Spain)

Dynamics between plants and soil control important processes such as community succession, nutrient cycling or resilience to environmental change. Until now, most research on plant-soil interactions has focused on uni-directional and species-specific effects of plants on soil and vice-versa, under controlled-conditions experiments, but little is known about the direct and indirect interactions between the plant community and the underlying soil under field conditions. We investigated these interactions in a semi-arid shrubland from NE Spain. We sampled plant biomass, nitrogen availability in soil, soil microbial biomass C, soil water infiltration capacity, soil bulk density and quality of plant tissue. These parameters were related to each other to build a statistical plant soil interaction model that was analyzed through regression and Structural Equation Modeling analyses. This statistical model was hypothesized to reveal important mechanisms for community regulation. Plant biomass was fundamentally dependent on water infiltration capacity and microbial biomass C was fundamentally dependent on nitrogen availability. Plant biomass interacted indirectly with microbial biomass C by directly affecting nitrogen stock and quality of plant tissue. Similarly, plant biomass modulated the soil bulk density. We demonstrated that vegetation has a preeminent role in the regulation of biological processes in this ecosystem through control on nutrient status, microbial biomass and mechanical soil conditions. Conclusions extracted from this study can be valuable in restoring and conserving similar ecosystems at risk of disappearing due to desertification.

Interaction of race and socioeconomic status as risk modulators of treatment delay and cancer-specific mortality in uterine cancer.

5595 Background: The majority of studies of uterine cancer combine high and low-grade histologies and do not sample a diverse cohort of patients. In many studies race is treated as biologic construct, when it may be better thought of as a proxy for socioeconomic inequity and deprivation. Socioeconomic (SE) deprivation may play a significant role in the disease trajectory of women with uterine cancer. Methods: Data were drawn from the Metropolitan Detroit Cancer Surveillance System which covers a tri-county area of approximately 4 million people. We included non-Hispanic Black (NHB) and White (NHW) women diagnosed with uterine cancer between 2010 and 2018. Poorly differentiated and undifferentiated endometrioid, serous, clear cell, mixed, carcinosarcoma and mucinous histologies were considered high grade. Patients diagnosed by death certificate, or with unknown stage or histology were excluded. Socioeconomic status was assessed using the Yost Score, an area-level composite measure of socioeconomic deprivation derived from census-tract data at cancer diagnosis. Lower Yost quintile indicates higher deprivation. Competing risk analysis was used to determine risk of uterine cancer specific mortality (reported as subdistribution hazard ratio [SHR]) and to assess statistical interaction between race and Yost score. Results: A total of 4,840 patients were identified. Race conferred significant increased risk of cancer-specific mortality (SHR 2.11, p &lt; 0.0001). Race and Yost score interacted to increase risk of cancer-specific mortality in NHB women in the lowest Yost quintile (SHR 2.23, p &lt; 0.0001) compared to NHW and NHB women in the highest quintiles. The interaction between race and Yost score persisted only among women with low grade cancers (SHR 1.7, p = 0.04). Time from diagnosis to surgery increased as Yost score decreased. Women in the lowest Yost quintile had lower likelihood of receiving surgery within 6 weeks of diagnosis (OR 0.74, p = 0.001). This effect persisted among women with low grade cancer (NHB OR 0.75, p = 0.014; lowest Yost quintile OR 0.68, p &lt; 0.0001). An association between race, Yost score and delays in time to surgery was not seen among women with high grade cancers. Conclusions: Race and Yost score, an area-based measure of socioeconomic deprivation, are associated with increased cancer-specific mortality risk among women with low grade cancer. NHB race and high socioeconomic deprivation are associated with delayed primary surgery. The interaction between race and socioeconomic deprivation may underlie known disparities in uterine cancer survival, particularly in low grade disease where there is the greatest opportunity for timely curative surgery.

Association Between Healthy Dietary Patterns and Markers of Oxidative Stress

ObjectivesOxidative stress is involved in chronic disease etiology and the aging process and is related to antioxidant intake. However, less is known about the relationship between dietary patterns and markers of oxidative stress. We assessed cross-sectionally the association between healthy dietary patterns [alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), alternative Healthy Eating Index (aHEI), and Healthy Eating Index 2015 (HEI-2015)] and urinary F2-isoprostanes (8-iso-PGF2α and 8-iso-PGF2α-M), which are established biomarkers of oxidative stress. MethodsData were obtained from 844 premenopausal and 454 postmenopausal women participating in the Sister Study who had urinary samples analyzed for F2-isoprostanes. Responses from a 110-item validated food frequency questionnaire (FFQ) at baseline were used to calculate dietary pattern scores. Concentrations of 8-iso-PGF2α and its metabolite (8-iso-PGF2α-M) were measured by GC/MS for samples from premenopausal women and LC/MS for samples from postmenopausal women. Multivariable linear regression models were used to estimate associations between aMED, DASH, aHEI, and HEI-2015 and urinary F2-isoprostanes among pre-menopausal and post-menopausal women separately. ResultsAmong premenopausal women, we observed significant inverse associations between the four dietary indices and mean 8-iso-PGF2α (aMED βQ4vsQ1: –0.15, 95% CI: –0.25, –0.05; DASH βQ4vsQ1: –0.15, 95% CI: –0.25, –0.25; aHEI βQ4vsQ1: –0.15, 95% CI: –0.25, –0.05; HEI-2015 βQ4vsQ1: –0.17, 95% CI: –0.27, –0.07). These associations were modified by age, education, income, and BMI, though there was no evidence of statistical interaction. In a sensitivity analysis, estimates did not substantially differ by the presence or absence of chronic disease. Among postmenopausal women, aHEI was associated with mean 8-iso-PGF2α and 8-iso-PGF2α-M (β8-iso-PGF2α: –0.003, 95% CI: –0.01, –0.005, β8-iso-PGF2α-M: –0.003, 95% CI: –0.01, –0.005). No other significant findings were observed among postmenopausal women. ConclusionsHealthy dietary patterns may be associated with reduced oxidative stress, particularly among premenopausal women. Funding SourcesNational Institute of Environmental Health Sciences, NIH Office of Dietary Supplements, Avon Foundation, T32 from NIH-NIGMS.

IV ASCORBATE REDUCTION OF ARDS MORTALITY IS CONTINGENT AND DOSE-DEPENDENT WITH THE DEGREE OF HYPEROXIC SUPPORT

TYPE: Late Breaking Abstract TOPIC: Critical Care PURPOSE: Several randomized trials have failed to demonstrate a mortality benefit of high-dose intravenous ascorbate (vitamin C) in patients with sepsis. Recent ex-vivo human lung experiments have revealed that ascorbate acts directly on lung endothelium in hyperoxic conditions. We hypothesized that similar effects may have occurred in CITRIS-ALI trial patients, a double-blind randomized controlled trial of high-dose intravenous vitamin C in patients with ARDS. METHODS: CITRIS-ALI patients were classified, post-hoc, into three groups: Low, moderate, and severe hyperoxia based upon FiO2 < 50%, 50-80%, and ≥ 80% respectively. Logistic regression analysis was applied to evaluate the statistical interactions between hyperoxic groups and 28-day mortality and marginal analysis was performed. RESULTS: Severe hyperoxia support significantly interacted with vitamin C administration instead of placebo (p<0.001). Patients with mild hyperoxia had mortality 30% (95% CI 13.6–46.4%) and 42.4% (95% CI 25.6–59.3) for placebo and vitamin C arms respectively, p=0.3. Moderate hyperoxia groups exhibited mortality of 41.4% (95% CI 23.5 – 59.3%) and 26.7% (95% CI10.8–42.5) for placebo and vitamin C arms, p=0.2. The highest degree of hyperoxia group had mortality 74% (95% CI 56–92%) and 14.3% (95% CI 0–29.3%) for placebo and vitamin C arms, p<0.001. CONCLUSIONS: These findings suggest that high-dose intravenous vitamin C reduction of ARDS mortality is significantly linked to the degree of hyperoxia required for support, being most significant in patients who require the highest levels of hyperoxia. CLINICAL IMPLICATIONS: These findings explain the heterogeneity of outcomes in vitamin C sepsis trials in contrast to CITRIS-ALI and could guide the design of future clinical trials. DISCLOSURE: Nothing to declare. KEYWORD: Hyperoxia

Cardiac-Brain Dynamics Depend on Context Familiarity and Their Interaction Predicts Experience of Emotional Arousal.

Our brain continuously interacts with the body as we engage with the world. Although we are mostly unaware of internal bodily processes, such as our heartbeats, they may be influenced by and in turn influence our perception and emotional feelings. Although there is a recent focus on understanding cardiac interoceptive activity and interaction with brain activity during emotion processing, the investigation of cardiac–brain interactions with more ecologically valid naturalistic emotional stimuli is still very limited. We also do not understand how an essential aspect of emotions, such as context familiarity, influences affective feelings and is linked to statistical interaction between cardiac and brain activity. Hence, to answer these questions, we designed an exploratory study by recording ECG and EEG signals for the emotional events while participants were watching emotional movie clips. Participants also rated their familiarity with the stimulus on the familiarity scale. Linear mixed effect modelling was performed in which the ECG power and familiarity were considered as predictors of EEG power. We focused on three brain regions, including prefrontal (PF), frontocentral (FC) and parietooccipital (PO). The analyses showed that the interaction between the power of cardiac activity in the mid-frequency range and the power in specific EEG bands is dependent on familiarity, such that the interaction is stronger with high familiarity. In addition, the results indicate that arousal is predicted by cardiac–brain interaction, which also depends on familiarity. The results support emotional theories that emphasize context dependency and interoception. Multimodal studies with more realistic stimuli would further enable us to understand and predict different aspects of emotional experience.

0598 Nocturnal Hypoxia and Right Ventricular Functional Characteristics in Connective Tissue Disease Associated Group 1 Pulmonary Arterial Hypertension

Abstract Introduction We extend our prior findings of nocturnal hypoxia association with right ventricular(RV) dysfunction in World Symposium Pulmonary Hypertension(WSPH) Group 1 Pulmonary Arterial Hypertension(PAH) to connective tissue disease(CTD)-PAH. Due to the autoimmune inflammatory pathophysiology in CTD, we postulate stronger associations with nocturnal hypoxia and RV dysfunction in CTD-PAH with less favorable transplant-free survival than non-CTD-PAH. Methods The multicenter PVDOMICS study(NCT02989887) includes Group 1 PAH patients &amp;gt;18 years with mean pulmonary artery pressure≥25mmHg, pulmonary capillary wedge pressure(PCWP) £15mmHg, and pulmonary vascular resistance &amp;gt;3 Woods units who underwent NOX-T3 home sleep study or other sleep testing within one year of enrollment. Linear regression models(beta coefficients,95%CI) were used to examine total recording time&amp;lt;90% SaO2(T90) with right ventricular(RV) functional measures: RV systolic pressure(RVSP,echocardiogram,mmHg), RV ejection fraction(RVEF, cardiac magnetic resonance imaging,%). Time-to-event analysis was performed examining T90 with transplant/death using Cox proportional hazard models in CTD-PAH and non-CTD-PAH. T90 interaction by CTD-PAH group was tested. Models were adjusted for age, sex, race, body mass index, PAH medications and supplemental oxygen/positive airway pressure. Results The analytic sample was comprised of CTD-PAH(n=45: 59.3±12.1 years,82.2% female) and non-CTD-PAH patients(n=142: 50.4 + 14.1,68.3% female). For each increase in T90 by 10%, RVSP increased 2.57mmHg(2.57[0.76, 4.38],p=0.006) and RVEF decreased 1.54%(-1.54[-2.58, -0.50],p=0.004) in CTD-PAH. For each increase in T90 by 10% in non-CTD-PAH, RVSP increased 2.34mmHg(2.34[1.30, 3.38],p&amp;lt;0.001) and RVEF decreased 0.72%(-0.72[-1.31,-0.13],p=0.017). The test for statistical interaction was not significant across CTD-PAH and non-CTD-PAH groups. There was similar mortality rates between CTD-PAH(22%) and non-CTD-PAH(24%). However, T90 was only associated with death/transplant in non-CTD-PAH with a 24% increased risk of transplant/death(HR=1.24, 95%CI:1.08-1.43,p=0.003). There was a borderline statistically significant interaction across groups in time-to-event analyses(p=0.092). Conclusion We identify that nocturnal hypoxia is associated with RV functional alterations irrespective of CTD contribution in Group 1 PAH after adjustment for confounding factors. Survival analyses demonstrated an association of the degree of nocturnal hypoxia and transplant/death only in the non-CTD-PAH group. Potential explanations for these unanticipated findings may be attributable to lower sample size of the CTD-PAH group or a true stronger hypoxia-mortality relationship driven by underlying pathophysiology of the non-CTD-PAH group. Support (If Any) NHLBI(U01HL125218,U01HL125205,U01HL125212,U01HL125208,U01HL125175, U01HL125215,U01HL125177); Pulmonary Hypertension Association

Treatment effect modifiers for individuals with acute low back pain: secondary analysis of the TARGET trial.

Treatment effect modifiers identify patient characteristics associated with treatment responses. The purpose of this secondary analysis was to identify potential treatment effect modifiers for disability from the TARGET trial that compared usual care (control) with usual care + psychologically informed physical therapy (PIPT). The sample consisted of a STarT Back tool identified high-risk patients with acute low back pain that completed Oswestry Disability Index (ODI) data at index visit and 6 months later (n = 1250). Candidate treatment effect modifiers were identified a priori and informed by the literature. Linear mixed models tested for treatment effect modification through tests of statistical interaction. All statistical interactions ( P ≤ 0.20) were stratified by modifier to inspect for specific effects ( P ≤ 0.05). Smoking was identified as a potential effect modifier (treatment * smoking interaction, P = 0.08). In participants who were smokers, the effect of PIPT was (ODI = 5.5; 95% CI: 0.6-10.4; P = 0.03) compared with usual care. In participants who were nonsmokers, the effect of PIPT was (ODI = 1.5; 95% CI: -1.4 to 4.4; P = 0.31) compared with usual care. Pain medication was also identified as a potential effect modifier (treatment × pain medication interaction, P = 0.10). In participants prescribed ≥3 pain medications, the effect of PIPT was (ODI = 7.1; 95% CI: -0.1 to 14.2; P = 0.05) compared with usual care. The PIPT effect for participants prescribed no pain medication was (ODI = 3.5; 95% CI: -0.4 to 7.4; P = 0.08) and for participants prescribed 1 to 2 pain medications was (ODI = 0.6; 95% CI: -2.5 to 3.7; P = 0.70) when compared with usual care. These findings may be used for generating hypotheses and planning future clinical trials investigating the effectiveness of tailored application of PIPT.

Effects of energy reduced diets including alternative protein sources and a phytogenic supplement on performance, carcass traits and digestibility in broiler chickens

Protein sources obtained from co-products might provide an alternative to soybean meal (SBM), counteracting the dependency on other countries and increasing the sustainability. In an energy reduced broiler diet (−0.72 MJ AME N ), a mixture of DDGS, sunflower meal and rapeseed meal was applied as alternative fiber rich protein source (APS) to replace 100% of SBM. Furthermore, the diets were supplemented with 0.04% of a lignan-rich phytogenic component derived from bark to improve the performance. The experimental diets were fed to 3,600 broilers (Ross 308, mixed sex) from day 11 to 36 posthatch (grower and finisher phase). Overall, the broilers responded to APS diets with a significantly increased daily feed intake and decreased body weight ( P < 0.05), which resulted in an impaired F:G ratio ( P < 0.05). The apparent total tract digestibility of dry matter, organic matter, and gross energy with APS diets decreased significantly. The replacement of SBM by APS resulted in higher gizzard weights ( P < 0.05), proventriculus weights ( P < 0.05) together with a decreased gizzard pH ( P < 0.05) and improved foot pad dermatitis score of broiler chickens ( P < 0.05). These findings suggest that the replacement of soybean meal with alternative protein sources in energy reduced diets destined for broilers negatively affects performance and digestibility, however, improves food pad health and upper intestinal tract characteristics. The supplementation with a phytogenic component, decreased feed intake in finisher phase, however improved F:G ratio and increased the breast weight ( P < 0.05). Furthermore, it indicated a positive statistical interaction with APS diets regarding certain digestibility values ( P < 0.05).

Fiuncho: a program for any-order epistasis detection in CPU clusters

Epistasis can be defined as the statistical interaction of genes during the expression of a phenotype. It is believed that it plays a fundamental role in gene expression, as individual genetic variants have reported a very small increase in disease risk in previous Genome-Wide Association Studies. The most successful approach to epistasis detection is the exhaustive method, although its exponential time complexity requires a highly parallel implementation in order to be used. This work presents Fiuncho, a program that exploits all levels of parallelism present in x86_64 CPU clusters in order to mitigate the complexity of this approach. It supports epistasis interactions of any order, and when compared with other exhaustive methods, it is on average 358, 7 and 3 times faster than MDR, MPI3SNP and BitEpi, respectively.

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease.

Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-β burden. Leveraging rich multimodal data from a population-based sample of older adults, we found that this novel tau PRS was a strong surrogate of tau PET deposition and captured a significant proportion of the variance in tau PET levels as compared with amyloid PET burden, APOE (apolipoprotein E) ε4 (the most common risk allele for AD), and a non-APOE PRS of clinical case-control AD risk variants. In independent validation samples, the tau PRS was associated with cerebrospinal fluid phosphorylated tau levels in one cohort and with postmortem Braak neurofibrillary tangle stage in another. We also observed an association of the tau PRS with longitudinal cognitive trajectories, including a statistical interaction of the tau PRS with amyloid burden on cognitive decline. Although additional study is warranted, these findings demonstrate the potential utility of a tau PRS for capturing the collective genetic background influencing tau deposition in the general population. In the future, a tau PRS could be leveraged for cost-effective screening and risk stratification to guide trial enrollment and clinical interventions in AD.

Thermodynamic geometry of harmonically trapped ideal quantum gases

In this paper, we consider the thermodynamic geometry of harmonic trapped Bose and Fermi gases. We construct a thermodynamic geometry for these systems and evaluate the corresponding metric tensor and thermodynamic curvature. By observing that the thermodynamic curvature of the trapped Bose (Fermi) gas is always positive (negative), we conclude that the trapping potential does not affect the intrinsic statistical interactions. By inspecting the singular points of the thermodynamic curvature, we argue that the confinement dimension and the frequency of the trapping potential change the critical value of fugacity for the Bose gas.

Combination studies of operating cell, inlet‐line, and humidification temperatures on performance of proton exchange membrane fuel cell

AbstractThe combined influence of factors, that is, operating cell temperature, humidification temperature (HT) (indirectly relative humidity), and reactant gas inlet‐line temperature on the performance of proton exchange membrane fuel cell was experimentally and statistically studied. A catalyst‐coated membrane, membrane electrode assembly, of 6.25 cm2 active area and 0.29 mgpt cm–2 catalyst loading was used in the study. Experimentally, the effect of individual factors and their combinations on cell performance was studied. Statistical analyses were carried out to find the main and interaction effects of different factors. Analysis of variance (ANOVA, 5% significance level, 95% confidence level) analysis, which was validated for homoscedasticity, was used to evaluate the significance of the main and interaction effects of factors. From the study, it was observed that the HT had a significant main effect (988 W m–2). Both interaction plots and ANOVA results revealed that the combination of operating cell and HT was the most significant. The study showed a very interesting observation that the statistical interaction effect (545 W m–2) was half of the experimental deviation value (1090 W m–2) between the summation of independent effects and the combined effect.