Lifestyle Risk Score: handling missingness of individual lifestyle components in meta-analysis of gene-by-lifestyle interactions

Recent studies consider lifestyle risk score (LRS), an aggregation of multiple lifestyle exposures, in identifying association of gene-lifestyle interaction with disease traits. However, not all cohorts have data on all lifestyle factors, leading to increased heterogeneity in the environmental exposure in collaborative meta-analyses. We compared and evaluated four approaches (Naïve, Safe, Complete and Moderator Approaches) to handle the missingness in LRS-stratified meta-analyses under various scenarios. Compared to “benchmark” results with all lifestyle factors available for all cohorts, the Complete Approach, which included only cohorts with all lifestyle components, was underpowered due to lower sample size, and the Naïve Approach, which utilized all available data and ignored the missingness, was slightly inflated. The Safe Approach, which used all data in LRS-exposed group and only included cohorts with all lifestyle factors available in the LRS-unexposed group, and the Moderator Approach, which handled missingness via moderator meta-regression, were both slightly conservative and yielded almost identical p values. We also evaluated the performance of the Safe Approach under different scenarios. We observed that the larger the proportion of cohorts without missingness included, the more accurate the results compared to “benchmark” results. In conclusion, we generally recommend the Safe Approach, a straightforward and non-inflated approach, to handle heterogeneity among cohorts in the LRS based genome-wide interaction meta-analyses.Subject terms: Genetics, Risk factors     

Exploring frontal asymmetry using functional near-infrared spectroscopy: a preliminary study of the effects of social anxiety during interaction and performance tasks

Preliminary studies examining brain function associated with social anxiety suggest the possibility of right-sided prefrontal activation associated with phobic stimulation. Although most existing neuroimaging techniques preclude participants from engaging in ecologically valid social tasks during assessment, functional near-infrared spectroscopy (fNIRS) is a promising new technique that permits such assessment. The present study investigated the utility of the fNIRS procedure and explored frontal asymmetry during in vivo social challenge tasks among female undergraduate students who scored in top and bottom percentiles on a social anxiety screening measure. Results revealed that participants in both groups experienced a significant increase in concentration of blood volume and oxygenated hemoglobin in the right hemisphere compared to the left hemisphere while giving a speech. Non-hemispheric effects were also observed. In addition, the high anxiety group showed a non-significant trend toward greater right frontal activity than the low anxiety group. This study highlights the utility of the fNIRS device in successfully assessing real-time changes in cerebrovascular response as a function of naturalistic social behavior, and supports the potential utility of this technology in the study of the neurophysiology of social anxiety.     

Do microscopic surgical margins matter for primary gastric gastrointestinal stromal tumor?

BackgroundAlthough tumor size and mitotic rate are established prognostic factors for worse survival in patients undergoing surgical resection for gastric gastrointestinal stromal tumors, the impact of microscopic margins, or R1 resection, is not completely established.MethodsPatients who received no neoadjuvant therapy and underwent surgical resection for stage I to III gastric gastrointestinal stromal tumors were identified from the 2010 to 2013 National Cancer Database and divided into 2 cohorts, R0 and R1 resections. Cox proportional hazards ratio and Kaplan Meier survival estimates were utilized to analyze 5-y overall survival.ResultsOf 2,084 patients, those with R1 resection (57, 2.7%) were more likely to have tumors >10 cm (28.1% vs 11.9%, odds ratio 3.51, P = .017) and stage III disease (26.3% vs 11.2%, odds ratio 2.26, P = .047). Although margin status was associated with higher risk tumors, it was not associated with receipt of adjuvant therapy. After multivariate Cox regression, R1 and R0 patients did not have a difference in 5-y overall survival (82.5% vs 88.6%, hazards ratio 1.26, P = .49). When stratified by stage of disease, there remained no difference in survival across all stages when comparing R1 and R0 patients.ConclusionPositive microscopic margins are uncommon but do not appear to impact survival outcomes in patients with resected localized gastric gastrointestinal stromal tumors.     

Non-Hispanic Blacks undergoing distal pancreatectomy have higher risk-adjusted rates of morbidity and are more likely to be high-cost outliers

BackgroundFew studies evaluate racial disparities in costs and clinical outcomes for patients undergoing distal pancreatectomy (DP).MethodsWe queried the Healthcare Cost and Utilization Project State Inpatient Databases to identify patients undergoing DP. Multivariable regression (MVR) was used to evaluate the association between race and postoperative outcomes.Results2,493 patients underwent DP; 265 (10%) were black, and 221 (8%) were of Hispanic ethnicity. On MVR, black and Hispanic patients were less likely than whites to undergo surgery in high volume centers (OR 0.53, 95% CI [0.40, 0.71]; OR 0.45, 95% CI [0.32, 0.62]). Black patients had a greater risk of postoperative complication (OR 1.40, 95% CI [1.07, 1.83]), 90-day readmission (OR 1.53, 95% CI [1.15, 2.02]), prolonged length of stay (OR 1.74, 95% CI [1.25–2.44]), and of being a high cost outliers (OR 1.40, 95% CI [1.02, 1.91]) compared to white patients.ConclusionBlack patients have increased risk of having a postoperative complication, prolonged hospitalization, and of being a high-cost outlier than non-Hispanic whites.     

Effects of oat beta-glucan on innate immunity and infection after exercise stress

PURPOSE: To test the effects of oat beta-glucan (ObetaG) on respiratory infection, macrophage antiviral resistance, and NK cytotoxicity. METHODS: Mice were randomly assigned to one of four groups: Ex-H2O, Ex-ObetaG, Con-H2O, or Con-ObetaG. ObetaG was fed in the drinking water for 10 d before intranasal inoculation of HSV-1 or sacrifice. Exercise consisted of treadmill running to volitional fatigue (approximately 140 min) for three consecutive days. Fifteen minutes after the last bout of exercise or rest, mice (N = 24) were intranasally inoculated with a standardized dose of HSV-1. Mice were monitored twice daily for morbidity and mortality. Additional mice were sacrificed after exercise, peritoneal macrophages were obtained via i.p. lavage and assayed for antiviral resistance to HSV-1 (N = 18), and spleens were harvested and assayed for NK cell cytotoxicity (N = 12). RESULTS: Exercise stress was associated with a 28% increase in morbidity (P = 0.036) and 18% increase in mortality (P = 0.15). Ingestion of ObetaG before infection prevented this increase in morbidity (P = 0.048) and mortality (P = 0.05). Exercise stress was associated with a decrease in macrophage antiviral resistance (P = 0.007), which was blocked by ingestion of ObetaG (P < 0.001). There were no effects of exercise or ObetaG on NK cytotoxicity. CONCLUSION: These data suggest that daily ingestion of ObetaG may offset the increased risk of URTI associated with exercise stress, which may be mediated, at least in part, by an increase in macrophage antiviral resistance.     

Detection of IgG-Associated Determinants in Reduced and Alkylated Preparations of Human IgG3 by Monoclonal Antibodies

Abstract. Using classical typing antisera, previous experiments have failed to demonstrate IgG3 in partially reduced and alkylated preparations of human IgG intended for intravenous application (IGIV). To establish that IgG3 is actually present in such preparations, we designed an enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies as solid-phase reagents and protein A-purified IgG3 as antigen. Three different samples of reduced and alkylated antigen were used: (1) IgG3 isolated from a ready-for-infusion IGIV; (2) IgG3 which was purified from an intramuscular (Cohn fraction II) IgG solution before being subjected to a mild reduction and alkylation procedure, and (3) completely reduced and alkylated IgG3. The reduction and alkylation procedure did not affect the solubility of IgG3, indicating that IGIV prepared in this manner should contain normal quantities of IgG3. In the ELISA, solid-phase monoclonals which were cross-reactive with multiple IgG subclasses clearly reacted with reduced and alkylated IgG3. Furthermore, there was no substantial difference between the quantities of modified and native antigen required for 50% maximal ELISA signal. In contrast, solid-phase monoclonals with IgG3-restricted specificity did not recognize reduced and alkylated material. These results indicate that IGIV prepared by reduction and alkylation has a normal IgG3 content and confirm that some IgG3-specific determinants are altered by the modification procedure.     

Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome‐wide associations

Genome‐wide association studies (GWAS) using high‐density genotyping platforms offer an unbiased strategy to identify new candidate genes for osteoporosis. It is imperative to be able to clearly distinguish signal from noise by focusing on the best phenotype in a genetic study. We performed GWAS of multiple phenotypes associated with fractures [bone mineral density (BMD), bone quantitative ultrasound (QUS), bone geometry, and muscle mass] with approximately 433,000 single‐nucleotide polymorphisms (SNPs) and created a database of resulting associations. We performed analysis of GWAS data from 23 phenotypes by a novel modification of a block clustering algorithm followed by gene‐set enrichment analysis. A data matrix of standardized regression coefficients was partitioned along both axes—SNPs and phenotypes. Each partition represents a distinct cluster of SNPs that have similar effects over a particular set of phenotypes. Application of this method to our data shows several SNP‐phenotype connections. We found a strong cluster of association coefficients of high magnitude for 10 traits (BMD at several skeletal sites, ultrasound measures, cross‐sectional bone area, and section modulus of femoral neck and shaft). These clustered traits were highly genetically correlated. Gene‐set enrichment analyses indicated the augmentation of genes that cluster with the 10 osteoporosis‐related traits in pathways such as aldosterone signaling in epithelial cells, role of osteoblasts, osteoclasts, and chondrocytes in rheumatoid arthritis, and Parkinson signaling. In addition to several known candidate genes, we also identified PRKCH and SCNN1B as potential candidate genes for multiple bone traits. In conclusion, our mining of GWAS results revealed the similarity of association results between bone strength phenotypes that may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in identifying novel genes and pathways that underlie several correlated phenotypes, as well as in deciphering genetic and phenotypic modularity underlying osteoporosis risk. © 2011 American Society for Bone and Mineral Research.     

Considerations for sentinel lymph node biopsy in breast cancer patients with biopsy proven axillary disease prior to neoadjuvant treatment

Background

Axillary disease can be downstaged with neoadjuvant treatment for breast cancer. We attempted to identify factors to consider in determining whether to perform a sentinel lymph node biopsy in patients with biopsy proven axillary metastases (cN+) prior to neoadjuvant treatment.