ABSTRACT
Objective: This study aims to address disparities in risk prediction by evaluating the performance of polygenic risk score (PRS) models using the 90 risk variants across 78 independent loci previously linked to Parkinson's disease (PD) risk across seven diverse ancestry populations. Methods: We conducted a multi-stage study, testing PRS models in predicting PD status across seven different ancestries applying three approaches: 1) PRS adjusted by gender and age; 2) PRS adjusted by gender, age and principal components (PCs); and 3) PRS adjusted by gender, age and percentage of population admixture. These models were built using the largest four population-specific summary statistics of PD risk to date (base data) and individual level data obtained from the Global Parkinson's Genetics Program (target data). We performed power calculations to estimate the minimum sample size required to conduct these analyses. A total of 91 PRS models were developed to investigate cumulative known genetic variation associated with PD risk and age of onset in a global context. Results: We observed marked heterogeneity in risk estimates across non-European ancestries, including East Asians, Central Asians, Latino/Admixed Americans, Africans, African admixed, and Ashkenazi Jewish populations. Risk allele patterns for the 90 risk variants yielded significant differences in directionality, frequency, and magnitude of effect. PRS did not improve in performance when predicting disease status using similar base and target data across multiple ancestries, demonstrating that cumulative PRS models based on current known risk are inherently biased towards European populations. We found that PRS models adjusted by percentage of admixture outperformed models that adjusted for conventional PCs in highly admixed populations. Overall, the clinical utility of our models in individually predicting PD status is limited in concordance with the estimates observed in European populations. Interpretation: This study represents the first comprehensive assessment of how PRS models predict PD risk and age at onset in a multi-ancestry fashion. Given the heterogeneity and distinct genetic architecture of PD across different populations, our assessment emphasizes the need for larger and diverse study cohorts of individual-level target data and well-powered ancestry-specific summary statistics. Our current understanding of PD status unraveled through GWAS in European populations is not generally applicable to other ancestries. Future studies should integrate clinical and *omics level data to enhance the accuracy and predictive power of PRS across diverse populations.
Subject(s)
Parkinson Disease , Humans , Parkinson Disease/etiology , alpha-Synuclein , Membrane Glycoproteins , GlycoproteinsABSTRACT
Abstract Introduction: Hyperglycemia has a negative impact on morbidity and mortality among patients with acute myocardial infarction (AMI). Objective: The objective of the study was to evaluate the impact of chronic hyperglycemia on in-hospital and short-term outcome in patients with acute anterior MI treated with streptokinase as thrombolytic therapy. Materials and methods: A total of 100 patients with acute anterior myocardial infarction received streptokinase as thrombolytic therapy were enrolled. They were classified according to the admission glycated hemoglobin (HbA1c) level into two groups: Chronic hyperglycemic group (HbA1c ≥ 6.5%) (36 patients) and non-chronic hyperglycemic group (HbA1c <6.5%) (64 patients). Laboratory investigation, conventional echocardiography, and speckle tracking were performed. Results: Global longitudinal strain (GLS) was significantly lower in patients with chronic hyperglycemia group compared to non-chronic hyperglycemia group (−13.52 ± 4.83 vs. −15.27 ± 1.87%, p = 0.009). In-hospital outcome: Heart failure and reinfarction were significantly increased in patients with chronic hyperglycemia (45.5 vs. 16.7% and 18.2 vs. 3.3%, respectively, p < 0.05). Six months outcome: Heart failure, left ventricular (LV) remodeling, arrhythmias, and bleeding rates were significantly increased in patients with chronic hyperglycemia (41.9 vs. 12.1%, 51.6 vs. 13.8%, 6.5 vs. 1.7%, and 6.5 vs. 1.7%, respectively, p < 0.05). GLS cutoff value ≥ −13.5 has the best diagnostic accuracy in predicting LV remodeling (sensitivity: 100%, specificity: 93%, positive predictive value: 94%, negative predictive value: 100%, accuracy: 97%, and area under curve: 0.99). Conclusion: Chronic hyperglycemia had higher incidence of heart failure and LV remodeling following acute MI. GLS can be used as a predictor of LV remodeling.
Resumen Introducción: La hiperglucemia tiene un impacto negativo sobre la morbimortalidad en pacientes con infarto agudo de miocardio. Objetivo: Evaluar el impacto de la hiperglucemia crónica sobre el desenlace hospitalario y a corto plazo en pacientes con infarto agudo de miocardio (IAM) anterior, tratados con estreptoquinasa como terapia trombolítica. Materiales y métodos: Se incluyeron un total de 100 pacientes con IAM anterior, quienes recibieron estreptoquinasa como terapia trombolítica. Se clasificaron en dos grupos de acuerdo con el nivel de hemoglobina glicosilada (HbA1c) al ingreso: el grupo con hiperglucemia crónica (HbA1c ≥ 6.5%) (36 pacientes) y el grupo sin hiperglucemia crónica (HbA1c <6.5%) (64 pacientes). Se practicaron estudios de laboratorio, y ecocardiografía convencional y con rastreo de marcas. Resultados: El strain longitudinal global (SLG) fue significativamente menor en pacientes del grupo con hiperglucemia crónica comparados con los del grupo sin hiperglucemia crónica (−13.52 ± 4.83 vs. −15.27 ± 1.87%, p = 0.009). Desenlace hospitalario: La falla cardíaca y el reinfarto aumentaron significativamente en los pacientes con hiperglucemia crónica (45.5 vs. 16.7% y 18.2 vs. 3.3%, respectivamente, p < 0.05). Desenlace a los seis meses: Las tasas de falla cardíaca, remodelación del ventrículo izquierdo (VI), arritmia, y sangrado aumentaron significativamente en pacientes con hiperglucemia crónica (41.9 vs. 12.1%, 51.6 vs. 13.8%, 6.5 vs. 1.7% y 6.5 vs. 1.7%, respectivamente, p < 0.05). El punto de corte de SLG ≥ −13.5 tiene la mejor precisión diagnóstica para predecir la remodelación del VI (sensibilidad: 100%, especificidad: 93%, VPP: 94%, VPN: 100%, precisión: 97% y área bajo la curva -AUC-: 0.99). Conclusión: La hiperglucemia crónica tuvo una mayor frecuencia de falla cardíaca y remodelación del VI luego de un infarto agudo de miocardio. El SLG se puede utilizar como predictor de la remodelación del VI.
ABSTRACT
This study was conducted to characterize the immunological parameters of chickens vaccinated with two formulated inactivated vaccines, water in oil (WO) and water in oil in water (WOW), prepared from velogenic Newcastle disease virus (vNDV) genotype VIIj isolated from outbreak among vaccinated chickens. Six groups (G1-G6) of commercial broiler chickens were established (n = 20). The G1-G3 were received homologous (WO and WOW) and heterologous (LaSota) inactivated vaccines, respectively. The G4 was vaccinated with live heterologous (LaSota) vaccine, while G5 and G6 were kept as control positive and control negative non-vaccinated groups. The antibody titers were measured against vNDV and LaSota antigens using hemagglutination inhibition (HI) test, the cytokine gene expressions of IFNγ, IL1ß, IL4, IL6, IL8, and IL18 were quantified using real-time RT-PCR, and the virus shedding was titrated on chicken embryo fibroblast cells after challenging by vNDV. The classical clinical signs and 100% mortality were observed only in G5 after vNDV challenging. The highest HI titers were detected in G1, G2, and G3 using NDV/168 antigen with no significant differences among them. These groups showed higher HI titer than G4 (2-4log2). Cytokine gene expression of IFNγ, IL1, IL6, IL8, and IL18 were significantly downregulated in vaccinated chickens with upregulation of IL4 than non-vaccinated challenge group. Viral shedding titers were significantly (0.0001, p ≤ 0.001) reduced in all samples form vaccinated chickens. In conclusion, the prepared vaccines produced highly efficient immunological responses and could be used for controlling the NDV infection.