Aim: We developed a new method to design objective, risk-based surveillance systems for non-indigenous species of invertebrates, vertebrates and plants, which might be introduced to a natural area ...through an industrial project; here, we provide the invertebrate case study. The method addresses issues common to complex surveillance design problems: a statistical standard (e.g. power); information gaps; multiple targets of unclear identity; a large surveillance area of heterogeneous risk of invasion; integrating multiple sources of surveillance data; optimizing for cost. Location: Barrow Island, Western Australia. Methods: We mapped the surveillance area for risk to target surveillance activities. An expert group identified a set of exemplar species and identified and characterized a set of detection methods for each, such that all potential invaders would be detected. We devised multi-element surveillance systems to detect each exemplar to the design power (0.8), then integrated them to a single system that was optimized for cost. Results: The surveillance system was deployed on the island to specification over 1 year, then reviewed for redesign in a second period. Main conclusions: The new method provided practical, risk-based surveillance system designs that met application requirements and overcame complex issues common to many surveillance applications. A review of experiences from surveillance in the first year led to practical improvements and design efficiencies.
IMPORTANCE: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide. OBJECTIVE: To ...benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies. DESIGN, SETTING, AND PARTICIPANTS: Extensive Veterans Health Administration’s electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. MAIN OUTCOMES AND MEASURES: Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. RESULTS: Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean SD age, 58 12.1 years) and 314 909 were of broadly European ancestry (mean SD age, 66.4 13.5 years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio OR, 1.81 95% CI, 1.76-1.87; P < 10−257) or bipolar disorder (OR, 1.42 95% CI, 1.39-1.44; P < 10−295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 95% CI, 1.29-1.42; P < 10−38) and bipolar disorder (OR, 1.16 95% CI, 1.11-1.12; P < 10−10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. CONCLUSIONS AND RELEVANCE: Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records–based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.
Maternal priming might enhance the beneficial nonspecific effects (NSEs) of live measles vaccination (MV). Children with a bacillus Calmette-Guérin (BCG) vaccine scar have a lower mortality rate than ...those without a scar that is not explained by protection against tuberculosis. We examined the hypothesis that BCG scarring would have a stronger effect on a child if the mother also had a BCG scar.
In a randomized controlled trial (RCT) of early MV in children aged 4.5 months, the BCG-scar status of the children and their mother were registered at enrollment at 4.5 months of age. The children were followed up until they were 36 months of age. Using a Cox proportional hazards model, we compared mortality rate ratios according to maternal and child BCG-scar status after adjusting for where the BCG vaccine was given (the national hospital or elsewhere). We censored for other interventions that have immunomodulating effects on child survival, including neonatal vitamin A supplementation and early MV.
A total of 2213 children had not received neonatal vitamin A supplementation and early MV; 83% of these children and 44% of the mothers had a BCG scar. Children whose mother had a BCG scar were not more likely to have a BCG scar than those whose mother did not have a BCG scar (risk ratio, 1.01 95% confidence interval (CI), 0.98-1.05). Among the children, having a BCG scar was associated with a 41% (95% CI, 5%-64%) lower mortality between the ages of 4.5 and 36 months. The reduction in mortality was 66% (95% CI, 33%-83%) if the mother also had a BCG scar but only 8% (95% CI, -83% to 53%) if the mother had no BCG scar (test of interaction, P = .04).
Maternal BCG priming might be important for the effect of BCG vaccination on child survival. Ensuring better BCG vaccine scarring among mothers and children could have a considerable effect on child mortality levels.
IMPORTANCE: Many psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association ...studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans’ health, such as suicide-related behaviors and substance use disorders (SUDs). OBJECTIVE: To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP). DESIGN, SETTING, AND PARTICIPANTS: A series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020. EXPOSURES: PGSs for EXT, depression, schizophrenia, and suicide attempt. MAIN OUTCOME(S) AND MEASURE(S): Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records. RESULTS: Within the MVP (560 824 patients; mean SD age, 67.9 14.3 years; 512 593 male 91.4%), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio OR, 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population.
Abstract
Aim
We developed a new method to design objective, risk‐based surveillance systems for non‐indigenous species of invertebrates, vertebrates and plants, which might be introduced to a natural ...area through an industrial project; here, we provide the invertebrate case study. The method addresses issues common to complex surveillance design problems: a statistical standard (e.g. power); information gaps; multiple targets of unclear identity; a large surveillance area of heterogeneous risk of invasion; integrating multiple sources of surveillance data; optimizing for cost.
Location
Barrow
I
sland,
W
estern
A
ustralia.
Methods
We mapped the surveillance area for risk to target surveillance activities. An expert group identified a set of exemplar species and identified and characterized a set of detection methods for each, such that all potential invaders would be detected. We devised multi‐element surveillance systems to detect each exemplar to the design power (0.8), then integrated them to a single system that was optimized for cost.
Results
The surveillance system was deployed on the island to specification over 1 year, then reviewed for redesign in a second period.
Main conclusions
The new method provided practical, risk‐based surveillance system designs that met application requirements and overcame complex issues common to many surveillance applications. A review of experiences from surveillance in the first year led to practical improvements and design efficiencies.
Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same ...time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.
In an open-label, pragmatic trial, patients with cardiovascular disease were randomly assigned to a strategy of 81 mg or 325 mg of aspirin daily. A substantial proportion of those assigned to the ...325-mg dose switched to the 81-mg dose, and there were no significant differences in cardiovascular events or major bleeding between the two groups.
Single-cell RNA sequencing (scRNA-Seq) has emerged as a powerful tool for understanding cellular heterogeneity and function. However the choice of sample multiplexing reagents can impact data quality ...and experimental outcomes. In this study, we compared various multiplexing reagents, including MULTI-Seq, Hashtag antibody, and CellPlex, across diverse sample types such as human peripheral blood mononuclear cells (PBMCs), mouse embryonic brain and patient-derived xenografts (PDXs). We found that all multiplexing reagents worked well in cell types robust to ex vivo manipulation but suffered from signal-to-noise issues in more delicate sample types. We compared multiple demultiplexing algorithms which differed in performance depending on data quality. We find that minor improvements to laboratory workflows such as titration and rapid processing are critical to optimal performance. We also compared the performance of fixed scRNA-Seq kits and highlight the advantages of the Parse Biosciences kit for fragile samples. Highly multiplexed scRNA-Seq experiments require more sequencing resources, therefore we evaluated CRISPR-based destruction of non-informative genes to enhance sequencing value. Our comprehensive analysis provides insights into the selection of appropriate sample multiplexing reagents and protocols for scRNA-Seq experiments, facilitating more accurate and cost-effective studies.
•Comparison of sample multiplexing reagents for single-cell RNA-Seq.•Evaluation of commercial fixed single-cell RNA-Seq kits.•Evaluation of CRISPR depletion of abundant transcripts.•Guidelines for implementation of cost saving measures for single-cell RNA-Seq.
Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and ...Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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