Genetic variation in FADS genes is associated with maternal long-chain PUFA status but not with cognitive development of infants in a high fish-eating observational study

AbstractLong-chain n-6 and n-3 PUFA (LC-PUFA), arachidonic acid (AA) (20:4n-6) and DHA (22:6n-3), are critical for optimal brain development. These fatty acids can be consumed directly from the diet, or synthesized endogenously from precursor PUFA by Δ-5 (encoded by FADS1) and Δ-6 desaturases (encoded by FADS2). The aim of this study was to determine the potential importance of maternal genetic variability in FADS1 and FADS2 genes to maternal LC-PUFA status and infant neurodevelopment in populations with high fish intakes. The Nutrition Cohorts 1 (NC1) and 2 (NC2) are longitudinal observational mother-child cohorts in the Republic of Seychelles. Maternal serum LC-PUFA was measured at 28 weeks gestation and genotyping for rs174537 (FADS1), rs174561 (FADS1), rs3834458 (FADS1-FADS2) and rs174575 (FADS2) was performed in both cohorts. The children completed the Bayley Scales of Infant Development II (BSID-II) at 30 months in NC1 and at 20 months in NC2. Complete data were available for 221 and 1310 mothers from NC1 and NC2 respectively. With increasing number of rs3834458 minor alleles, maternal concentrations of AA were significantly decreased (NC1 p=0.004; NC2 p<0.001) and precursor:product ratios for linoleic acid (LA) (18:2n-6)-to-AA (NC1 p<0.001; NC2 p<0.001) and α-linolenic acid (ALA) (18:3n-3)-to-DHA were increased (NC2 p=0.028). There were no significant associations between maternal FADS genotype and BSID-II scores in either cohort. A trend for improved PDI was found among infants born to mothers with the minor rs3834458 allele.In these high fish-eating cohorts, genetic variability in FADS genes was associated with maternal AA status measured in serum and a subtle association of the FADS genotype was found with neurodevelopment

Local Cross-Validated Smoothing Parameter Estimation for Linear Smoothers

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biostatistics & Computational Biology, 2017.Nonparametrically estimating a regression function with varying degrees of smoothness or heteroscedasticity can benefit from a smoother that uses a data-adaptive smoothing parameter function to efficiently capture the local features. Leave-one-out cross-validation (LOO CV) has been used to select global smoothing parameters, as it is expected to estimate the true mean integrated squared error (MISE), but it often leads to undersmoothing in cases with sharp changes in smoothness and heteroscedasticity. Oracle simulations show that simply moving from a globally-chosen to a locally-chosen smoothing parameter yields a reduction in MISE. We explore LOO CV as a method of estimating the mean squared error as a function of the point of estimation, MSE(x), in order to estimate a smoothing parameter function. We identify a relationship between the Squared Leave-One-Out cross-validated Residuals (SLOORs) and MSE(x) for general linear smoothers. We use this identity to estimate MSE(x) and obtain improved smoothing parameter function estimates. This proposal presents a portfolio of smoothers based on local polynomials and natural cubic smoothing splines that estimate and use a data-adaptive smoothing parameter function by employing Local Cross-Validation (LCV). Data is locally weighted by a proposed truncated gaussian kernel function with sample-size adaptive truncation thresholds. The proposed Local Cross-Validated Polynomial smoothing algorithm (LCVPoly) estimates and uses an adaptive bandwidth function for any specified polynomial order. LCVPoly can further select the preferred global polynomial order and adaptive orders are explored to permit greater flexibility. The relationship of the variance function estimation problem to the mean function estimation problem is evident in the SLOOR-MSE identity. These methods only require specification of bandwidth bounds and polynomial orders. Available methods intended to handle underlying functions of varying smoothness are reviewed as competitors to our proposed algorithms. While local polynomials use both bandwidth and polynomial order to control smoothness, smoothing splines use a single smoothing parameter. Because of this, we propose a single version of our Local Cross-Validated Spline (LCVSpline) smoothing algorithm to estimate and use an adaptive degree-of-freedom function. As smoothing splines are linear smoothers, the SLOOR-MSE relationship holds here as well and we can use the result for degree-of-freedom function estimation. Electrocardiograms (ECGs) measured over a 24-hour period are heteroscedastic and can be very noisy, which can mask short-term cardiovascular events of interest. This type of data can benefit from a smoother that can pick up both short-term events and long-term changes while appropriately smoothing out the noise. Current techniques to smooth ECG data use a moving median smoother with no guide on the size of the moving window. We show how our proposed methods and other available methods perform on a dataset of over 80,000 heart inter-beat intervals. In addition to this data, we also employ our methods on the well-known motorcycle acceleration data set typically used to demonstrate spatially adaptive smoothers

Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

To access publisher's full text version of this article click on the hyperlink belowPURPOSE: Due to the complex pharmacokinetic profiles of phenytoin (PHT) and fosphenytoin (FOS), achieving sustained, targeted serum PHT levels in the first day of use is challenging. METHODS: A population based approach was used to analyze total serum PHT (tPHT) level within 2-24h of PHT/FOS loading with or without supplementary maintenance or additional loading doses among PHT-naïve patients in the acute hospital setting. Adequate tPHT serum level was defined as ≥20μg/mL. RESULTS: Among 494 patients with 545 tPHT serum levels obtained in the first 2-24h after the loading dose (LD), tPHT serum levels of eitherClinical & Translational Science Institute (CTSI) of the University of Rocheste

Transcriptomic Biomarkers to Discriminate Bacterial from Nonbacterial Infection in Adults Hospitalized with Respiratory Illness

Lower respiratory tract infection (LRTI) commonly causes hospitalization in adults. Because bacterial diagnostic tests are not accurate, antibiotics are frequently prescribed. Peripheral blood gene expression to identify subjects with bacterial infection is a promising strategy. We evaluated whole blood profiling using RNASeq to discriminate infectious agents in adults with microbiologically defined LRTI. Hospitalized adults with LRTI symptoms were recruited. Clinical data and blood was collected, and comprehensive microbiologic testing performed. Gene expression was measured using RNASeq and qPCR. Genes discriminatory for bacterial infection were identified using the Bonferroni-corrected Wilcoxon test. Constrained logistic models to predict bacterial infection were fit using screened LASSO. We enrolled 94 subjects who were microbiologically classified; 53 as non-bacterial and 41 as bacterial . RNAseq and qPCR confirmed significant differences in mean expression for 10 genes previously identified as discriminatory for bacterial LRTI. A novel dimension reduction strategy selected three pathways (lymphocyte, α-linoleic acid metabolism, IGF regulation) including eleven genes as optimal markers for discriminating bacterial infection (naïve AUC = 0.94; nested CV-AUC = 0.86). Using these genes, we constructed a classifier for bacterial LRTI with 90% (79% CV) sensitivity and 83% (76% CV) specificity. This novel, pathway-based gene set displays promise as a method to distinguish bacterial from nonbacterial LRTI

Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study

<div><p>Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89) and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001). Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12–2.25) independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034). Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005). We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in <i>MAGEC3</i>) reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75–4.65) advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.</p></div

Representative registry pedigrees.

<p>Ovarian cancers are represented by teal circles, breast cancers by pink circles, prostate cancers by blue squares and prophylactic oophorectomies by grey circles. The earliest of age of onset, prophylaxis, death or last follow up is indiciated below individuals as well as oophorectomies (ooph.) and one heterozygous variant carrier (A/G).</p

Age-of-onset by genotype and familial pattern.

<p>Age-of-onset by genotype and familial pattern.</p

Cancer rates given an affected daughter or sister.

<p>Cancer rates given an affected daughter or sister.</p