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BJOG : An International Journal of... Nov 2023Brain anomalies (BAs) have been the focus of research, as they have a high impact on fetal health but therapeutic and diagnostic approaches are limited. (Review)
Review
Diagnostic yield of prenatal exome sequencing in the genetic screening of fetuses with brain anomalies detected by MRI and ultrasonography: A systematic review and meta-analysis.
BACKGROUND
Brain anomalies (BAs) have been the focus of research, as they have a high impact on fetal health but therapeutic and diagnostic approaches are limited.
OBJECTIVES
In this study, the application and efficiency of exome sequencing (ES) in detecting different cases of BAs in fetuses were evaluated and compared with chromosomal microarray analysis (CMA).
SEARCH STRATEGY
To conduct this study, three databases including PubMed, Web of Science and Embase were utilised with the keywords 'prenatal', 'diagnoses', 'brain anomalies' and 'exome sequencing'.
SELECTION CRITERIA
Studies were included based on the STARD checklist, for which the ES and CMA diagnostic yields were calculated.
DATA COLLECTION AND ANALYSIS
Meta-analysis was performed on the included studies using a random-effects model and subgroup analysis to define the risk difference between them.
MAIN RESULTS
We included 11 studies representing 779 fetuses that implemented ES along with imaging techniques. The pooled ES diagnostic yield in fetuses with BAs detected through magnetic resonance imaging (MRI) and ultrasonography was 26.53%, compared with 3.46% for CMA. The risk difference between ES and CMA for complex BAs was 0.36 [95% confidence interval (CI) 0.24-0.47], which was higher than for single BAs (0.22; 95% CI 0.18-0.25].
CONCLUSIONS
ES is a useful method with a significantly higher diagnostic yield than CMA for genetic assessment of fetuses with complex BAs detected by imaging techniques. Moreover, ES could be applied to suspected fetuses with related family histories to predict congenital diseases with high efficiency.
PubMed: 37932235
DOI: 10.1111/1471-0528.17710 -
BMJ Global Health Oct 2023Microarray patches (MAPs) deliver vaccines to the epidermis and the upper dermis, where abundant immune cells reside. There are several potential benefits to using MAPs,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Microarray patches (MAPs) deliver vaccines to the epidermis and the upper dermis, where abundant immune cells reside. There are several potential benefits to using MAPs, including reduced sharps risk, thermostability, no need for reconstitution, tolerability and self-administration. We aimed to explore and evaluate the immunogenicity, safety, usability and acceptability of MAPs for vaccination.
METHODS
We searched CINAHL, Cochrane Library, Ovid Embase, Ovid MEDLINE and Web of Science from inception to January 2023. Eligibility criteria included all research studies in any language, which examined microarrays or microneedles intended or used for vaccination and explored immunogenicity, safety, usability or acceptability in their findings. Two reviewers conducted title and abstract screening, full-text reviewing and data extraction.
RESULTS
Twenty-two studies were included (quantitative=15, qualitative=2 and mixed methods=5). The risk of bias was mostly low, with two studies at high risk of bias. Four clinical trials were included, three using influenza antigens and one with Japanese encephalitis delivered by MAP. A meta-analysis indicated similar or higher immunogenicity in influenza MAPs compared with needle and syringe (N&S) (standardised mean difference=10.80, 95% CI: 3.51 to 18.08, p<0.00001). There were no significant differences in immune cell function between MAPs and N&S. No serious adverse events were reported in MAPs. Erythema was more common after MAP application than N&S but was brief and well tolerated. Lower pain scores were usually reported after MAP application than N&S. Most studies found MAPs easy to use and highly acceptable among healthcare professionals, laypeople and parents.
CONCLUSION
MAPs for vaccination were safe and well tolerated and evoked similar or enhanced immunogenicity than N&S, but further research is needed. Vaccine uptake may be increased using MAPs due to less pain, enhanced thermostability, layperson and self-administration. MAPs could benefit at-risk groups and low and middle-income countries.
PROSPERO REGISTRATION NUMBER
CRD42022323026.
Topics: Humans; Influenza, Human; Vaccination; Vaccines; Pain
PubMed: 37827725
DOI: 10.1136/bmjgh-2023-012247 -
Ultrasound in Obstetrics & Gynecology :... Jan 2024First, to determine the incremental yield of whole-genome sequencing (WGS) over quantitative fluorescence polymerase chain reaction (QF-PCR)/chromosomal microarray... (Meta-Analysis)
Meta-Analysis Review
Incremental yield of whole-genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta-analysis.
OBJECTIVES
First, to determine the incremental yield of whole-genome sequencing (WGS) over quantitative fluorescence polymerase chain reaction (QF-PCR)/chromosomal microarray analysis (CMA) with and without exome sequencing (ES) in fetuses, neonates and infants with a congenital anomaly that was or could have been detected on prenatal ultrasound. Second, to evaluate the turnaround time (TAT) and quantity of DNA required for testing using these pathways.
METHODS
This review was registered prospectively in December 2022. Ovid MEDLINE, EMBASE, MEDLINE (Web of Science), The Cochrane Library and ClinicalTrials.gov databases were searched electronically (January 2010 to December 2022). Inclusion criteria were cohort studies including three or more fetuses, neonates or infants with (i) one or more congenital anomalies; (ii) an anomaly which was or would have been detectable on prenatal ultrasound; and (iii) negative QF-PCR and CMA. In instances in which the CMA result was unavailable, all cases of causative pathogenic copy number variants > 50 kb were excluded, as these would have been detectable on standard prenatal CMA. Pooled incremental yield was determined using a random-effects model and heterogeneity was assessed using Higgins' I test. Subanalyses were performed based on pre- or postnatal cohorts, cases with multisystem anomalies and those meeting the NHS England prenatal ES inclusion criteria.
RESULTS
A total of 18 studies incorporating 902 eligible cases were included, of which eight (44.4%) studies focused on prenatal cohorts, incorporating 755 cases, and the remaining studies focused on fetuses undergoing postmortem testing or neonates/infants with congenital structural anomalies, constituting the postnatal cohort. The incremental yield of WGS over QF-PCR/CMA was 26% (95% CI, 18-36%) (I = 86%), 16% (95% CI, 9-24%) (I = 85%) and 39% (95% CI, 27-51%) (I = 53%) for all, prenatal and postnatal cases, respectively. The incremental yield increased in cases in which sequencing was performed in line with the NHS England prenatal ES criteria (32% (95% CI, 22-42%); I = 70%) and in those with multisystem anomalies (30% (95% CI, 19-43%); I = 65%). The incremental yield of WGS for variants of uncertain significance (VUS) was 18% (95% CI, 7-33%) (I = 74%). The incremental yield of WGS over QF-PCR/CMA and ES was 1% (95% CI, 0-4%) (I = 47%). The pooled median TAT of WGS was 18 (range, 1-912) days, and the quantity of DNA required was 100 ± 0 ng for WGS and 350 ± 50 ng for QF-PCR/CMA and ES (P = 0.03).
CONCLUSION
While WGS in cases with congenital anomaly holds great promise, its incremental yield over ES is yet to be demonstrated. However, the laboratory pathway for WGS requires less DNA with a potentially faster TAT compared with sequential QF-PCR/CMA and ES. There was a relatively high rate of VUS using WGS. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Cohort Studies; DNA; Exome Sequencing; Microarray Analysis; Prenatal Diagnosis; Ultrasonography; Infant
PubMed: 37725747
DOI: 10.1002/uog.27491 -
Journal of Translational Medicine Aug 2023Accurately predicting the outcome of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) remains hitherto challenging. This study aims to Construct and Validate...
BACKGROUND
Accurately predicting the outcome of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) remains hitherto challenging. This study aims to Construct and Validate a Robust Prognostic Model for IDH wild-type GBM (COVPRIG) for the prediction of overall survival using a novel metric, gene-gene (G × G) interaction, and explore molecular and cellular underpinnings.
METHODS
Univariate and multivariate Cox regression of four independent trans-ethnic cohorts containing a total of 800 samples. Prediction efficacy was comprehensively evaluated and compared with previous models by a systematic literature review. The molecular underpinnings of COVPRIG were elucidated by integrated analysis of bulk-tumor and single-cell based datasets.
RESULTS
Using a Cox-ph model-based method, six of the 93,961 G × G interactions were screened to form an optimal combination which, together with age, comprised the COVPRIG model. COVPRIG was designed for RNA-seq and microarray, respectively, and effectively identified patients at high risk of mortality. The predictive performance of COVPRIG was satisfactory, with area under the curve (AUC) ranging from 0.56 (CGGA693, RNA-seq, 6-month survival) to 0.79 (TCGA RNAseq, 18-month survival), which can be further validated by decision curves. Nomograms were constructed for individual risk prediction for RNA-seq and microarray-based cohorts, respectively. Besides, the prognostic significance of COVPRIG was also validated in GBM including the IDH mutant samples. Notably, COVPRIG was comprehensively evaluated and externally validated, and a systemic review disclosed that COVPRIG outperformed current validated models with an integrated discrimination improvement (IDI) of 6-16%. Moreover, integrative bioinformatics analysis predicted an essential role of METTL1 neural-progenitor-like (NPC-like) malignant cell in driving unfavorable outcome.
CONCLUSION
This study provided a powerful tool for the outcome prediction for IDH wild-type GBM, and preliminary molecular underpinnings for future research.
Topics: Humans; Glioblastoma; Isocitrate Dehydrogenase; Brain Neoplasms; Prognosis; Nomograms; Methyltransferases
PubMed: 37553713
DOI: 10.1186/s12967-023-04382-2 -
Ultrasound in Obstetrics & Gynecology :... Mar 2024To determine the incremental diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in cases of prenatally diagnosed agenesis of... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To determine the incremental diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in cases of prenatally diagnosed agenesis of the corpus callosum (ACC) and to identify the associated genes and variants.
METHODS
A systematic search was performed to identify relevant studies published up until June 2022 using four databases: PubMed, SCOPUS, Web of Science and The Cochrane Library. Studies in English reporting on the diagnostic yield of ES following negative CMA in prenatally diagnosed partial or complete ACC were included. Authors of cohort studies were contacted for individual participant data and extended cohorts were provided for two of them. The increase in diagnostic yield with ES for pathogenic/likely pathogenic (P/LP) variants was assessed in all cases of ACC, isolated ACC, ACC with other cranial anomalies and ACC with extracranial anomalies. To identify all reported genetic variants, the systematic review included all ACC cases; however, for the meta-analysis, only studies with ≥ three ACC cases were included. Meta-analysis of proportions was employed using a random-effects model. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria.
RESULTS
A total of 28 studies, encompassing 288 prenatally diagnosed ACC cases that underwent ES following negative CMA, met the inclusion criteria of the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC with a full phenotypic description. There were 15 studies, encompassing 268 cases, that reported on ≥ three ACC cases and were included in the meta-analysis. Of all the included cases, 43% had a P/LP variant on ES. The highest yield was for ACC with extracranial anomalies (55% (95% CI, 35-73%)), followed by ACC with other cranial anomalies (43% (95% CI, 30-57%)) and isolated ACC (32% (95% CI, 18-51%)).
CONCLUSIONS
ES demonstrated an incremental diagnostic yield in cases of prenatally diagnosed ACC following negative CMA. While the greatest diagnostic yield was observed in ACC with extracranial anomalies and ACC with other central nervous system anomalies, ES should also be considered in cases of isolated ACC. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; Humans; Pregnancy; Agenesis of Corpus Callosum; Corpus Callosum; Exome Sequencing
PubMed: 37519216
DOI: 10.1002/uog.27440 -
Endocrine, Metabolic & Immune Disorders... 2024Several studies have identified CD163 as a potential mediator of diabetes mellitus through an immune-inflammation. Further study is necessary to identify its specific...
BACKGROUND
Several studies have identified CD163 as a potential mediator of diabetes mellitus through an immune-inflammation. Further study is necessary to identify its specific mechanism.
OBJECTIVES
In this study, we aimed to investigate CD163 as a potential biomarker associated with immune inflammation in diabetes mellitus through a systematic review and bioinformatics analysis.
METHODS
We searched PubMed, Web of Science, the Cochrane Library, and Embase databases with a time limit of September 2, 2022. Furthermore, we conducted a systematic search and review based on PRISMA guidelines. Additionally, diabetic gene expression microarray datasets GSE29221, GSE30528, GSE30529, and GSE20966 were downloaded from the GEO database (http://www.ncbi.nlm.nih.gov/geo) for bioinformatics analysis. The PROSPERO number for this study is CRD420222347160.
RESULTS
Following the inclusion and exclusion criteria, seven articles included 1607 patients, comprising 912 diabetic patients and 695 non-diabetic patients. This systematic review found significantly higher levels of CD163 in diabetic patients compared to non-diabetic patients. People with diabetes had higher levels of CRP expression compared to the control group. Similarly, two of the three papers that used TNF- α as an outcome indicator showed higher expression levels in diabetic patients. Furthermore, IL-6 expression levels were higher in diabetic patients than in the control group. A total of 62 samples were analyzed by bioinformatics (33 case controls and 29 experimental groups), and 85 differential genes were identified containing CD163. According to the immune cell correlation analysis, CD163 was associated with macrophage M2, γδ T lymphocytes, macrophage M1, and other immune cells. Furthermore, to evaluate the diagnostic performance of CD163, we validated it using the GSE20966 dataset. In the validation set, CD163 showed high diagnostic accuracy.
CONCLUSION
This study suggests CD163 participates in the inflammatory immune response associated with diabetes mellitus and its complications by involving several immune cells. Furthermore, the results suggest CD163 may be a potential biomarker reflecting immune inflammation in diabetic mellitus.
Topics: Humans; Biomarkers; Computational Biology; Diabetes Mellitus; Inflammation; Macrophages
PubMed: 37455460
DOI: 10.2174/1871530323666230714162324 -
Genes May 2023Skeletal dysplasias are a group of diseases characterized by bone and joint abnormalities, which can be detected during prenatal ultrasound. Next-generation sequencing... (Review)
Review
Diagnostic Yield of Exome Sequencing in Fetuses with Sonographic Features of Skeletal Dysplasias but Normal Karyotype or Chromosomal Microarray Analysis: A Systematic Review.
Skeletal dysplasias are a group of diseases characterized by bone and joint abnormalities, which can be detected during prenatal ultrasound. Next-generation sequencing has rapidly revolutionized molecular diagnostic approaches in fetuses with structural anomalies. This review studies the additional diagnostic yield of prenatal exome sequencing in fetuses with prenatal sonographic features of skeletal dysplasias. This was a systematic review by searching PubMed for studies published between 2013 and July 2022 that identified the diagnostic yield of exome sequencing after normal karyotype or chromosomal microarray analysis (CMA) for cases with suspected fetal skeletal dysplasias based on prenatal ultrasound. We identified 10 out of 85 studies representing 226 fetuses. The pooled additional diagnostic yield was 69.0%. The majority of the molecular diagnoses involved de novo variants (72%), while 8.7% of cases were due to inherited variants. The incremental diagnostic yield of exome sequencing over CMA was 67.4% for isolated short long bones and 77.2% for non-isolated cases. Among phenotypic subgroup analyses, features with the highest additional diagnostic yield were an abnormal skull (83.3%) and a small chest (82.5%). Prenatal exome sequencing should be considered for cases with suspected fetal skeletal dysplasias with or without a negative karyotype or CMA results. Certain sonographic features, including an abnormal skull and small chest, may indicate a potentially higher diagnostic yield.
Topics: Pregnancy; Female; Humans; Prenatal Diagnosis; Exome Sequencing; Microarray Analysis; Fetus; Osteochondrodysplasias; Karyotype
PubMed: 37372383
DOI: 10.3390/genes14061203 -
Brain Sciences Jun 2023Around the world, more the 700,000 individuals die by suicide every year. It is necessary to understand the mechanisms associated with suicidal behavior. Recently, an... (Review)
Review
Around the world, more the 700,000 individuals die by suicide every year. It is necessary to understand the mechanisms associated with suicidal behavior. Recently, an increase in gene expression studies has been in development. Through a systematic review, we aimed to find a candidate gene in gene expression studies on postmortem brains of suicide completers. Databases were systematically searched for published studies. We performed an online search using PubMed, Scopus and Web of Science databases to search studies up until May 2023. The terms included were "gene expression", "expressed genes", "microarray", "qRT-PCR", "brain samples" and "suicide". Our systematic review included 59 studies covering the analysis of 1450 brain tissues from individuals who died by suicide. The majority of gene expression profiles were obtained of the prefrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex, ventral prefrontal cortex and orbital frontal cortex area. The most studied mRNAs came of genes in glutamate, γ-amino-butyric acid and polyamine systems. mRNAs of genes in the brain-derived neurotrophic factor, tropomyosin-related kinase B (TrkB), HPA axis and chemokine family were also studied. On the other hand, psychiatric comorbidities indicate that suicide by violent death can alter the profile of mRNA expression.
PubMed: 37371384
DOI: 10.3390/brainsci13060906 -
American Journal of Obstetrics &... Sep 2023This study aimed to determine the incremental diagnostic yield of prenatal exome sequencing after negative chromosomal microarray analysis results in prenatally... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study aimed to determine the incremental diagnostic yield of prenatal exome sequencing after negative chromosomal microarray analysis results in prenatally diagnosed bilateral severe ventriculomegaly or hydrocephalus; another objective was to categorize the associated genes and variants.
DATA SOURCES
A systematic search was performed to identify relevant studies published until June 2022 using 4 databases (Cochrane Library, Web of Science, Scopus, and MEDLINE).
STUDY ELIGIBILITY CRITERIA
Studies in English reporting on the diagnostic yield of exome sequencing following negative chromosomal microarray analysis results in cases of prenatally diagnosed bilateral severe ventriculomegaly were included.
METHODS
Authors of cohort studies were contacted for individual participant data, and 2 studies provided their extended cohort data. The incremental diagnostic yield of exome sequencing was assessed for pathogenic/likely pathogenic findings in cases of: (1) all severe ventriculomegaly; (2) isolated severe ventriculomegaly (as the only cranial anomaly); (3) severe ventriculomegaly with other cranial anomalies; and (4) nonisolated severe ventriculomegaly (with extracranial anomalies). To be able to identify all reported genetic associations, the systematic review portion was not limited to any minimal severe ventriculomegaly case numbers; however, for the synthetic meta-analysis, we included studies with ≥3 severe ventriculomegaly cases. Meta-analysis of proportions was done using a random-effects model. Quality assessment of the included studies was performed using the modified STARD (Standards for Reporting of Diagnostic Accuracy Studies) criteria.
RESULTS
A total of 28 studies had 1988 prenatal exome sequencing analyses performed following negative chromosomal microarray analysis results for various prenatal phenotypes; this included 138 cases with prenatal bilateral severe ventriculomegaly. We categorized 59 genetic variants in 47 genes associated with prenatal severe ventriculomegaly along with their full phenotypic description. There were 13 studies reporting on ≥3 severe ventriculomegaly cases, encompassing 117 severe ventriculomegaly cases that were included in the synthetic analysis. Of all the included cases, 45% (95% confidence interval, 30-60) had positive pathogenic/likely pathogenic exome sequencing results. The highest yield was for nonisolated cases (presence of extracranial anomalies; 54%; 95% confidence interval, 38-69), followed by severe ventriculomegaly with other cranial anomalies (38%; 95% confidence interval, 22-57) and isolated severe ventriculomegaly (35%; 95% confidence interval, 18-58).
CONCLUSION
There is an apparent incremental diagnostic yield of prenatal exome sequencing following negative chromosomal microarray analysis results in bilateral severe ventriculomegaly. Although the greatest yield was found in cases of nonisolated severe ventriculomegaly, consideration should also be given to performing exome sequencing in cases of isolated severe ventriculomegaly as the only brain anomaly identified on prenatal imaging.
Topics: Pregnancy; Female; Humans; Exome Sequencing; Hydrocephalus; Cohort Studies
PubMed: 37311485
DOI: 10.1016/j.ajogmf.2023.101048 -
Frontiers in Genetics 2023Genetic variants cause a significant portion of developmental disorders and intellectual disabilities (DD/ID), but clinical and genetic heterogeneity makes...
Genetic variants cause a significant portion of developmental disorders and intellectual disabilities (DD/ID), but clinical and genetic heterogeneity makes identification challenging. Compounding the issue is a lack of ethnic diversity in studies into the genetic aetiology of DD/ID, with a dearth of data from Africa. This systematic review aimed to comprehensively describe the current knowledge from the African continent on this topic. Applicable literature published up until July 2021 was retrieved from PubMed, Scopus and Web of Science databases, following PRISMA guidelines, focusing on original research reports on DD/ID where African patients were the focus of the study. The quality of the dataset was assessed using appraisal tools from the Joanna Briggs Institute, whereafter metadata was extracted for analysis. A total of 3,803 publications were extracted and screened. After duplicate removal, title, abstract and full paper screening, 287 publications were deemed appropriate for inclusion. Of the papers analysed, a large disparity was seen between work emanating from North Africa compared to sub-Saharan Africa, with North Africa dominating the publications. Representation of African scientists on publications was poorly balanced, with most research being led by international researchers. There are very few systematic cohort studies, particularly using newer technologies, such as chromosomal microarray and next-generation sequencing. Most of the reports on new technology data were generated outside Africa. This review highlights how the molecular epidemiology of DD/ID in Africa is hampered by significant knowledge gaps. Efforts are needed to produce systematically obtained high quality data that can be used to inform appropriate strategies to implement genomic medicine for DD/ID on the African continent, and to successfully bridge healthcare inequalities.
PubMed: 37234869
DOI: 10.3389/fgene.2023.1137922