Nevin Manimala

J Thromb Haemost. 2022 Mar 14. doi: 10.1111/jth.15698. Online ahead of print.

ABSTRACT

BACKGROUND: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.

OBJECTIVES: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.

METHODS: Summary statistics from genome wide-association studies (GWAS) from 7 hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and 3 major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 x 10^-9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27).

RESULTS: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes.

CONCLUSIONS: The discovery of 4 novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

PMID:35285134 | DOI:10.1111/jth.15698

Pharmacoepidemiol Drug Saf. 2022 Mar 14. doi: 10.1002/pds.5427. Online ahead of print.

ABSTRACT

PURPOSE: This study aimed to examine trends in valproate use among women of childbearing potential aged 16-44 years (WCBP) in Ireland following two European-directed regulatory interventions in December 2014 and April 2018.

METHODS: This was a repeated cross-sectional study using monthly national pharmacy claims data, to examine trend changes in the prevalence of valproate use among WCBP pre and post two separate regulatory events in December 2014 and April 2018. Annual population estimates from the Central Statistics Office were used to calculate the prevalence rate per 1000 eligible women. Segmented regression analysis of interrupted time series with negative binomial regression was used to examine rates for WCBP aged 16-44 years, and by 10-year age groups. Prevalence ratios (PR) are presented with 95% confidence intervals (CIs).

RESULTS: Among WCBP aged 16-44 years, there was no statistically significant change in the month-to-month prevalence ratio in the post- compared to pre-December 2014 intervention period. A significant decline was, however, observed in the post-, compared to pre-April 2018 intervention period (PR = 0.998, [95%CIs: 0.996, 1.000]; p = 0.029). Among those aged 16-24 years, a significant decreasing trend in the month-to-month prevalence ratio was found in the post- compared to pre-December 2014 intervention period (PR = 0.991, [95%CIs: 0.984, 0.998], p <0.01). A marginal effect was observed in the post- compared to pre-April 2018 intervention period for those aged 25-34 years (PR = 0.996, [95%CIs: 0.992, 1.000]; p = 0.048).

CONCLUSION: Although no evidence of change was observed following the December 2014 intervention period, a significant decline in the prevalence ratio of valproate use was observed after the 2018 intervention, which may reflect the introduction of the most recent contraindication measures. This article is protected by copyright. All rights reserved.

PMID:35285110 | DOI:10.1002/pds.5427

J Clin Lab Anal. 2022 Mar 13:e24334. doi: 10.1002/jcla.24334. Online ahead of print.

ABSTRACT

BACKGROUND: Among patients with diabetic retinopathy (DR), no proof was available to confirm the prognostic significance of the neutrophil percentage-to-albumin ratio (NPAR). We hypothesized that NPAR plays a role in the incidence of DR in diabetic patients.

METHODS: We extracted all diabetes mellitus (DM) data from the National Health and Nutrition Examination Survey (NHANES) database between 1999 and 2018, NPAR was expressed as neutrophil percentage/albumin. Multivariable logistic regression and generalized additive model were utilized for the purpose of examining the correction between NPAR levels and DR. Subgroup analysis of the associations between NPAR and DR was carried out to investigate if the impact of the NPAR varied among different subgroups.

RESULTS: An aggregate of 5850 eligible participants were included in the present research. The relationship between NPAR levels and DR was positive linear. In the multivariate analysis, following the adjustment for confounders (gender, white blood cell, age, monocyte percent, red cell distribution width, eosinophils percent, bicarbonate, body mass index, iron, glucose, basophils percent, total bilirubin, creatinine, and chloride), higher NPAR was an independent risk factor for DR compared to lower NPAR (OR, 95% CI: 1.18, 1.00-1.39; 1.24, 1.04-1.48). For the purpose of sensitivity analysis, we found a trend of consistency (p for trend: 0.0190). The results of the subgroup analysis revealed that NPAR did not exert any statistically significant interactions with any of the other DR risk variables.

CONCLUSIONS: Elevated NPAR is associated with an elevated risk of occurrence of DR in diabetic patients.

PMID:35285099 | DOI:10.1002/jcla.24334

Exp Dermatol. 2022 Mar 13. doi: 10.1111/exd.14563. Online ahead of print.

NO ABSTRACT

PMID:35285091 | DOI:10.1111/exd.14563

Pediatr Dermatol. 2022 Mar 14. doi: 10.1111/pde.14978. Online ahead of print.

ABSTRACT

BACKGROUND: Cutaneous changes in obese adults have been investigated in numerous studies, but this issue has not been adequately investigated in children.

OBJECTIVES: We aimed to determine the prevalence of skin manifestations in children with obesity by comparing them to normal-weight children.

METHODS: A cross-sectional study was conducted between June 2017 and January 2019 in which 82 children with obesity and 86 normal-weight healthy control children were enrolled. Study participants had detailed full-body skin examinations performed by the same dermatologist; mycological and Wood’s lamp examinations were performed when necessary. Sociodemographic and anthropometric measurements of the participants were recorded.

RESULTS: Striae distensae were the most common skin manifestation in children with obesity; striae were significantly higher in the obese than in the control group (72% vs. 26.7%, p < .001). The anatomical distribution of the striae distensae in the groups differed significantly. Striae distensae were most commonly observed on the buttocks in the control group, while the thighs were the most common site in the obese group. Acanthosis nigricans (63.4% vs. 3.5%, p < .001), acrochordons (17.1% vs. 1.2%, p < .001), keratosis pilaris (32.9% vs. 17.4%, p = .021), intertrigo (11% vs. 0%, p = .001), folliculitis (31.7% vs. 5.8%, p < .001), seborrheic dermatitis (12.2% vs. 3.5%, p = .035) and facial erythema (7.3% vs. 0%, p = .012) were found to be statistically significantly more common in the obese group compared to the control group.

CONCLUSIONS: Obesity in children is associated with numerous cutaneous manifestations. Further study is needed to identify whether weight loss can reduce skin manifestations in obese children.

PMID:35285075 | DOI:10.1111/pde.14978

Biom J. 2022 Mar;64(3):481-505. doi: 10.1002/bimj.202000249. Epub 2021 Nov 10.

ABSTRACT

In this paper, we present the Type I multivariate zero-inflated Conway-Maxwell-Poisson distribution, whose development is based on the extension of the Type I multivariate zero-inflated Poisson distribution. We developed important properties of the distribution and present a regression model. The AIC and BIC criteria are used to select the best fitted model. Two real data sets have been used to illustrate the proposed model. Moreover, we conclude by stating that the Type I multivariate zero-inflated Conway-Maxwell-Poisson distribution produces a better fitted model for multivariate count data with excess of zeros.

PMID:35285065 | DOI:10.1002/bimj.202000249

Biom J. 2022 Mar;64(3):557-576. doi: 10.1002/bimj.202100023. Epub 2021 Dec 1.

ABSTRACT

In this article, we address the problem of simultaneous testing hypothesis about mean and covariance matrix for repeated measures data when both the mean vector and covariance matrix are patterned. In particular, tests about the mean vector under block circular and doubly exchangeable covariance structures have been considered. The null distributions are established for the corresponding likelihood ratio test statistics, and expressions for the exact or near-exact probability density and cumulative distribution functions are obtained. The application of the results is illustrated by both a simulation study and a real-life data example.

PMID:35285064 | DOI:10.1002/bimj.202100023

Biom J. 2022 Mar;64(3):598-616. doi: 10.1002/bimj.202000222. Epub 2021 Dec 11.

ABSTRACT

The between-study variance or heterogeneity variance is an important parameter in random effects meta-analysis. This paper uses an M-estimation framework to introduce and discuss variance estimators for quantifying the uncertainty in estimates of the heterogeneity variance using the noniterative generalized method of moments estimator and some related method of moments estimators. An example is used to further illustrate the variance estimators, and simulation results are presented for assessing the empirical properties of the proposed variance estimators.

PMID:35285063 | DOI:10.1002/bimj.202000222

J Med Virol. 2022 Mar 13. doi: 10.1002/jmv.27721. Online ahead of print.

ABSTRACT

Crimean Congo hemorrhagic fever (CCHF) is an acute viral infection that can cause death. The detection of host transcriptome is important for understanding differences in pathogenesis of the disease. Long noncoding RNAs (lncRNAs) regulate gene expression in different biological processes. They have also emerged as a key molecules for therapeutic target. We investigated the lncRNA gene expression profiles by utilizing the microarray for the first time in CCHF. LncRNAs were determined by the comparisons between case-control, fatal case-control, and fatal case-nonfatal case. Quantitative polymerase chain reaction (qPCR) was applied to validate the microarray results of some lncRNAs. In our study, 39 lncRNAs (5 downregulated, 34 upregulated) were found to be significantly regulated in the cases when compared to the controls (p<0,05; FC≥2). One hundred ten lncRNAs exhibited a statistically significant difference between fatal cases and controls. FER1L4, ECRP and LOC100133669 are important lncRNAs in both case and fatal case groups compared with controls. These lncRNAs may be considered as important therapeutic targets for the CCHF in further studies. This article is protected by copyright. All rights reserved.

PMID:35285033 | DOI:10.1002/jmv.27721

JPEN J Parenter Enteral Nutr. 2022 Mar 13. doi: 10.1002/jpen.2374. Online ahead of print.

ABSTRACT

BACKGROUND: Parenteral nutrition associated cholestasis (PNAC) in the neonatal intensive care unit (NICU) causes significant morbidity and associated healthcare costs. Laboratory detection of PNAC currently relies on elevated serum conjugated bilirubin levels in the aftermath of impaired bile flow. Here, we sought to identify fecal biomarkers, which when integrated with clinical data would better predict risk for developing PNAC.

METHODS: Using untargeted metabolomics in 200 serial stool samples from 60 infants, we applied statistical and machine learning approaches to identify clinical features and metabolic biomarkers with the greatest associative potential for risk of developing PNAC. Stools were collected prospectively from infants receiving parenteral nutrition (PN) with soybean oil-based lipid emulsion at a level IV NICU.

RESULTS: Low birthweight, extreme prematurity, longer duration of PN, and greater number of antibiotic courses were all risk factors for PNAC (p < 0.05). We identified 78 stool biomarkers with early predictive potential (p < 0.05). From these 78 biomarkers, we further identified 12 sphingomyelin lipids with high association for the development of PNAC in pre-cholestasis stool samples when combined with birth anthropometry.

CONCLUSIONS: We demonstrate the potential for stool metabolomics to enhance early identification of PNAC risk. Earlier detection of high-risk infants would empower proactive mitigation with alterations to PN for at-risk infants and optimization of caloric nutrition with PN for infants at lower risk. This article is protected by copyright. All rights reserved.

PMID:35285019 | DOI:10.1002/jpen.2374