Genetic association studies making use of high-throughput genotyping arrays need to process large amounts of data in the order of millions of markers per experiment. The first step of any analysis ...with genotyping arrays is typically the conduct of a thorough data clean up and quality control to remove poor quality genotypes and generate metrics to inform and select individuals for downstream statistical analysis. We have developed pyGenClean, a bioinformatics tool to facilitate and standardize the genetic data clean up pipeline with genotyping array data. In conjunction with a source batch-queuing system, the tool minimizes data manipulation errors, accelerates the completion of the data clean up process and provides informative plots and metrics to guide decision making for statistical analysis.
pyGenClean is an open source Python 2.7 software and is freely available, along with documentation and examples, from http://www.statgen.org.
Oligodendrocytes are the myelin‐forming cells of the central nervous system that facilitate transmission of axonal electrical impulses. Using transgenic mice expressing 2′,3′ cyclic nucleotide 3′ ...phosphodiesterase (CNPase)‐enhanced green fluorescent protein, a three‐dimensional reconstruction tool and analysis, we illustrate that three morphologically different oligodendrocyte types exist in the hippocampus. Those of the ramified type have the most numerous processes, the largest cell body, occupy the largest area and form beaded‐like structures, due to mitochondria aggregates, along the processes. Stellar‐shaped oligodendrocytes have smaller cell bodies and their processes cover a significantly smaller area. Those of the smooth subtype have a small cell body with at most two processes. In addition to these types, a large number of oligodendrocytes were found that faintly express CNPase‐enhanced green fluorescent protein. More than 50% of the faint type colocalized with NG2 and 91% with oligodendrocyte transcription factor‐2, whereas 94% of NG2‐immunoreactive and 45% of oligodendrocyte transcription factor‐2‐immunoreactive cells were faintly CNPase‐enhanced green fluorescent protein positive. Based on the complexity of the overall structure, the three types probably represent stages of a maturation process such that one subtype can morph into another. Thus, the least complex ‘smooth’ cell would represent the youngest oligodendrocyte that matures into the stellar type and eventually progresses to become the most complex ramified oligodendrocyte. Investigation of the distribution pattern revealed that the highest density of oligodendrocytes was found in the stratum lacunosum‐moleculare and the hilar region. The distribution analysis of oligodendrocyte subclasses revealed a tendency for different cell types to segregate in large non‐overlapping areas. This observation suggests that morphologically, and possible functionally, different oligodendrocytes are topographically segregated.
Left-sided congenital heart disease (CHD) encompasses a spectrum of malformations that range from bicuspid aortic valve to hypoplastic left heart syndrome. It contributes significantly to infant ...mortality and has serious implications in adult cardiology. Although left-sided CHD is known to be highly heritable, the underlying genetic determinants are largely unidentified. In this study, we sought to determine the impact of structural genomic variation on left-sided CHD and compared multiplex families (464 individuals with 174 affecteds (37.5%) in 59 multiplex families and 8 trios) to 1,582 well-phenotyped controls. 73 unique inherited or de novo CNVs in 54 individuals were identified in the left-sided CHD cohort. After stringent filtering, our gene inventory reveals 25 new candidates for LS-CHD pathogenesis, such as SMC1A, MFAP4, and CTHRC1, and overlaps with several known syndromic loci. Conservative estimation examining the overlap of the prioritized gene content with CNVs present only in affected individuals in our cohort implies a strong effect for unique CNVs in at least 10% of left-sided CHD cases. Enrichment testing of gene content in all identified CNVs showed a significant association with angiogenesis. In this first family-based CNV study of left-sided CHD, we found that both co-segregating and de novo events associate with disease in a complex fashion at structural genomic level. Often viewed as an anatomically circumscript disease, a subset of left-sided CHD may in fact reflect more general genetic perturbations of angiogenesis and/or vascular biology.
Background Explicit criteria for judging medication safety and use issues in patients with chronic kidney disease (CKD) are lacking. Study Design Quality improvement report. Setting & Participants ...Nephrologists (n = 4), primary care physicians (n = 2), hospital pharmacists with expertise in nephrology (n = 4), and community pharmacists (n = 2). The PAIR (Pharmacotherapy Assessment in Chronic Renal Disease) criteria were applied retrospectively to 90 patients with CKD in a randomized study. Quality Improvement Plan Development of an explicit set of criteria to enable rapid and systematic detection of drug-related problems (DRPs). Using a RAND method, experts judged the clinical significance of DRPs and the appropriateness of a community pharmacist intervention. The PAIR criteria include 50 DRPs grouped into 6 categories. Outcomes DRPs detected using the PAIR criteria compared with implicit clinical judgment by nephrology pharmacists. Measurements Prevalence of DRPs and reliability, validity, and responsiveness of the PAIR criteria. Results A mean of 2.5 DRPs/patient (95% CI, 2.0-3.1) was identified based on the PAIR criteria compared with 3.9 DRPs/patient (95% CI, 3.4-4.5) based on clinical judgment of nephrology pharmacists. Inter-rater reliability coefficients (κ) by PAIR category varied from 0.80-1.00, with an intraclass correlation coefficient (ICC) of 0.93 (95% CI, 0.89-0.95) for total DRPs per patient. Test-retest reliability coefficients by category varied from 0.74-1.00, with an ICC of 0.91 (95% CI, 0.82-0.96) for total DRPs per patient. During the study, the mean number of DRPs per patient did not change significantly when assessed using the PAIR criteria and clinical judgment. Limitation The prevalence of PAIR DRPs may be underestimated due to the retrospective nature of the validation. Conclusion The prevalence of DRPs requiring the intervention of community pharmacists is high in patients with CKD. The PAIR criteria are reliable, but their responsiveness remains to be shown.
Introduction:
Chronic kidney disease (CKD) patients are multimorbid elderly at high risk of drug‐related problems. A Web‐based training program was developed based on a list of significant ...drug‐related problems in CKD patients requiring a pharmaceutical intervention. The objectives were to evaluate the impact of the program on community pharmacists' knowledge and skills and their satisfaction with the training.
Methods:
Pharmacists were randomized to the training program or the control group. Training comprised a 60‐minute Web‐based interactive session supported by a clinical guide. Pharmacists completed a questionnaire on knowledge (10 multiple‐choice questions) and skills (2 clinical vignettes) at baseline and a second time within 1 month. Trained pharmacists completed a written satisfaction questionnaire. Semidirected telephone interviews were conducted with 8 trained pharmacists. Changes in knowledge and skills scores were compared between the groups.
Results:
Seventy pharmacists (training: 52; control: 18) were recruited; the majority were women with <15 years' experience. Compared with the control group, an adjusted incremental increase in the knowledge score (22%; 95% confidence interval CI: 16%–27%) and skills score (24%; 95% CI: 16%–33%) was observed in the training group. Most pharmacists (87%–100%) rated each aspect of the program “excellent'' or “very good.” Additional training and adding a discussion forum were suggested to complement the program.
Discussion:
Pharmacists like the Web‐based continuing education program. Over a short time span, the program improved their knowledge and skills. Its impact on their clinical practices and quality of medication use in CKD patients remains to be assessed.
Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to ...identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10−8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.
Searching for genes in which loss-of-function mutations confer protection against disease is a strategy to identity drug targets. This study reports an association between loss-of-function mutations ...in
ANGPTL4
and protection against coronary artery disease.
Although genomewide association studies have identified more than 56 loci associated with the risk of coronary artery disease,
1
–
3
the disease-associated variants are typically common (minor-allele frequency >5%) and located in noncoding sequences; this has made it difficult to pinpoint causal genes and affected pathways. This lack of a causal mechanism has in part hindered the immediate translation of the findings of genomewide association studies into new therapeutic targets. However, the discovery of rare or low-frequency coding-sequence variants that affect the risk of coronary artery disease has facilitated advances in the prevention and treatment of disease. The most recent example . . .
Hepatic lipid homeostasis depends on intracellular pathways that respire fatty acid in peroxisomes and mitochondria, and on systemic pathways that secrete fatty acid into the bloodstream, either free ...or condensed in very-low-density lipoprotein (VLDL) triglycerides. These systemic and intracellular pathways are interdependent, but it is unclear whether and how they integrate into a single cellular circuit. Here, we report that mouse liver wrappER, a distinct endoplasmic reticulum (ER) compartment with apparent fatty acid- and VLDL-secretion functions, connects peroxisomes and mitochondria. Correlative light electron microscopy, quantitative serial section electron tomography and three-dimensional organelle reconstruction analysis show that the number of peroxisome-wrappER-mitochondria complexes changes throughout fasting-to-feeding transitions and doubles when VLDL synthesis stops following acute genetic ablation of Mttp in the liver. Quantitative proteomic analysis of peroxisome-wrappER-mitochondria complex-enriched fractions indicates that the loss of Mttp upregulates global fatty acid β-oxidation, thereby integrating the dynamics of this three-organelle association into hepatic fatty acid flux responses. Therefore, liver lipid homeostasis occurs through the convergence of systemic and intracellular fatty acid-elimination pathways in the peroxisome-wrappER-mitochondria complex.
Genetic sex and psychosocial factors relating to sex and gender influence a person's risk of developing neurocognitive impairment (NCI). Yet their role in mechanisms underlying APOE-ɛ4 ...pathophysiology of NCI remains unclear. We explore whether sex and gender independently modify the association between APOE-ɛ4 and NCI.
We conducted effect modification analyses in N=364,793 participants from the UK Biobank pan-ancestry dataset (return #2442) without prevalent cardiovascular disease or NCI. APOE-ɛ4 carrier status was inferred based on diplotypes derived from phased genotypes. NCI cases were identified in hospitalization, mortality, and self-report questionnaire datasets. Gender was measured using a previously constructed literature-based femininity score (FS) that leverages six psychosocial factors. We estimated adjusted generalized linear models (GLM) for NCI, as random effects for ancestry groups were not informative. To evaluate APOE-ɛ4 effect modification by gender, we stratified models by sex and introduced interaction terms for APOE-ɛ4 and FS. We estimated conditional effects corrected for multiplicity to illustrate modification across FS. To evaluate APOE-ɛ4 effect modification by sex, we introduced interaction terms for APOE-ɛ4 and sex and conditioned on FS. Sensitivity analyses were conducted with NCI cases identified from primary care data (N=169,125).
We identified N=6,123 participants with incident NCI in the sex-combined sample (1.7%), of which 2,990 were female. APOE-ɛ4 was associated with increased risk of NCI in females (p
Both sex and gender influence the effect of APOE-ɛ4 on NCI in diverse ancestries. More analyses are needed to clarify mechanisms by which gender influences risk conferred by APOE-ɛ4 in both sexes.
Abstract
We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical ...trial. We found a significant association at 5p13.3 (rs1173773;
P
= 4.94 × 10
–8
) near the natriuretic peptide receptor 3 gene (
NPR3
). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331;
P
= 2.95 × 10
–8
) in interaction with colchicine (
P
= 1.19 × 10
–5
) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.
PDF
