Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Descriptive Comparison of Two Models of Tele-Critical Care Delivery in a Large Multi-Hospital Health Care System.

Introduction: The Society of Critical Care Medicine Tele-Critical Care (TCC) Committee has identified the need for rigorous comparative research of different TCC delivery models to support the development of best practices for staffing, application, and approaches to workflow. Our objective was to describe and compare outcomes between two TCC delivery models, TCC with 24/7 Bedside Intensivist (BI) compared with TCC with Private Daytime Attending Intensivist (PI) in relation to intensive care unit (ICU) and hospital mortality, ICU and hospital length of stay (LOS), cost, and complications across the spectrum of routine ICU standards of care. Methods: Observational cohort study at large health care system in 12 ICUs and included patients, ≥18, with Acute Physiology and Chronic Health Evaluation (APACHE) IVa scores and predictions (October 2016-June 2019). Results: Of the 19,519 ICU patients, 71.7% (n = 13,993) received TCC with 24/7 BI while 28.3% (n = 5,526) received TCC with PI. ICU and Hospital mortality (4.8% vs. 3.1%, p < 0.0001; 12.6% vs. 8.1%, p < 0.001); and ICU and Hospital LOS (3.2 vs. 2.4 days, p < 0.001; 9.8 vs. 7.2 days, p < 0.001) were significantly higher among 24/7 BI compared with PI. The APACHE observed/expected ratios (odds ratio [OR]; 95% confidence interval [CI]) for ICU mortality (0.62; 0.58-0.67) vs. (0.53; 0.46-0.61) and Hospital mortality (0.95; 0.57-1.48) vs. (0.77; 0.70-0.84) were significantly different for 24/7 BI compared with PI. Multivariate mixed models that adjusted for confounders demonstrated significantly greater odds of (OR; 95% CI) ICU mortality (1.58; 1.28-1.93), Hospital mortality (1.52; 1.33-1.73), complications (1.55; 1.18-2.04), ICU LOS [3.14 vs. 2.59 (1.25; 1.19-1.51)], and Hospital LOS [9.05 vs. 7.31 (1.23; 1.21-1.25)] among 24/7 BI when compared with PI. Sensitivity analyses adjusting for ICU admission within 24 h of hospital admission, receiving active ICU treatments, nighttime admission, sepsis, and highest third acute physiology score indicated significantly higher odds for 24/7 BI compared with PI. Conclusion: Our comparison demonstrated that TCC delivery model with PI provided high-quality care with significant positive effects on outcomes. This suggests that TCC delivery models have broad-ranging applicability and benefits in routine critical care, thus necessitating progressive research in this direction.

A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer's Disease in African Ancestry.

African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (ß = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (ß = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (ß = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (ß = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

Common topics discerned in ethics in epidemiology and public health syllabi: in-depth review.

This commentary reviews ethics in epidemiology and public health (PH) syllabi collected in 2011 and 2018. The syllabi repository was an American College of Epidemiology (ACE) Ethics Committee project to support institutions and faculty introducing, furthering or improving ethics in epidemiology and public health courses. Of 83 syllabi from 52 accredited public health schools and programs, 80 were reviewed to identify the most common ethics topics. The extracted information was categorized into eight main groups: (1) ethical/moral foundations and theories; (2) case studies in epidemiology/PH; (3) ethical issues in PH practice; (4) ethical issues in general epidemiologic/PH research; (5) ethical issues in specific research areas; (6) ethical issues in information technology; (7) ethical issues in other emerging topics in epidemiology/PH; and (8) others. The frequency of topics in each category was computed, and common topics were presented. Ethical issues absent from the syllabi were inferred. This commentary is intended to promote a dialog among those desiring to elevate epidemiology and public health ethics to an educational level commensurate with its importance.