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Prenatal Diagnosis Aug 2023Unexplained stillbirth is defined as a stillbirth with no known cause after the exclusion of common causes, including obstetric complications, infections, placental... (Review)
Review
Unexplained stillbirth is defined as a stillbirth with no known cause after the exclusion of common causes, including obstetric complications, infections, placental insufficiency or abruption, umbilical cord complications, and congenital abnormalities with or without known genetic cause. More than 60% of stillbirth cases remain unexplained. The aim of this systematic review was to investigate the known genetic causes of unexplained stillbirth cases and to evaluate the current position and future directions for the use of genetic and genomic testing in expanding the knowledge in this field. A systematic search through several databases was performed using the keywords genetics and stillbirths in humans. Different methods to detect various types of causal genetic aberrations have been used in the past decades, from standard karyotyping to novel methods such as chromosomal microarray analysis and next generation sequencing technologies. Apart from common chromosomal aneuploidies, a promising hypothesis about genetic causes included genes related to cardiomyopathies and channelopathies. However, these were tested in the research settings, since molecular karyotyping is currently the standard approach in the routine evaluation of genetic causes of stillbirth. Hereby, we provide evidence that expanding knowledge using novel genetic and genomic testing might uncover new genetic causes of unexplained stillbirth.
Topics: Humans; Female; Pregnancy; Stillbirth; Placenta; Aneuploidy; Databases, Factual; Genetic Profile
PubMed: 37072878
DOI: 10.1002/pd.6354 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... May 2021Chromosome microarray analysis (CMA) has become the first-tier testing for chromosomal abnormalities and copy number variations (CNV). This review described the clinical...
Chromosome microarray analysis (CMA) has become the first-tier testing for chromosomal abnormalities and copy number variations (CNV). This review described the clinical validation of CMA, the development and updating of technical standards and guidelines and their diagnostic impacts. The main focuses were on the development and updating of expert consensus, practice resources, and a series of technical standards and guidelines through systematic review of case series with CMA application in the literature. Expert consensus and practice resource supported the use of CMA as the first-tier testing for detecting chromosomal abnormalities and CNV in developmental and intellectual disabilities, multiple congenital anomalies and autism. The standards and guidelines have been applied to pre- and postnatal testing for constitutional CNV and tumor testing for acquired CNV. CMA has significantly improved the diagnostic yields but still needs to overcome its technical limitations and face challenges of new technologies. Guiding and governing CMA through expert consensus, practice resource, standards and guidelines in the United States has provided effective and safe diagnostic services to patients and their families, reliable diagnosis on related genetic diseases for clinical database and basic research, and references for clinical translation of new technologies.
Topics: Child; Chromosome Aberrations; Chromosomes; DNA Copy Number Variations; Developmental Disabilities; Humans; Intellectual Disability; Microarray Analysis; United States
PubMed: 33974247
DOI: 10.3760/cma.j.cn511374-20200924-00690 -
Critical Reviews in Oncogenesis 2019The purpose of this meta-analysis is to evaluate the association of Epstein-Barr virus (EBV) with oral squamous cell carcinoma (OSCC). We searched the electronic... (Meta-Analysis)
Meta-Analysis
The purpose of this meta-analysis is to evaluate the association of Epstein-Barr virus (EBV) with oral squamous cell carcinoma (OSCC). We searched the electronic scientific databases of PubMed and Scopus and included a total of 53 studies that were published from 1990 to 2019. The analysis yielded a 45.37% (95% confidence interval [CI]: 38.90-51.84; p < 0.001) overall pooled prevalence of EBV. Studies that used the applied methods of in situ hybridization, polymerase chain reaction, immunology, or RNA microarray showed the following pooled prevalence: 46.08%, 40.32, 54.97%, and 74.89%, respectively. EBV-infected individuals have a 2.5 higher risk for developing OSCC (odds ratio: 2.57; 95% CI: 1.23% to 5.36%; p < 0.001). The present meta-analysis supports the hypothesis of EBV association with OSCC, pointing to this virus as a risk factor for neoplasia. Our findings also suggest that EBV latent transcripts (latent membrane protein 1, EBV nuclear antigen 1 and 2, and EBV-encoded small RNAs) have an important role in this process. Furthermore, novel advancements could arise from large and standardized studies that are constructed to probe for other latent gene expression, eliminate confounding factors (tobacco, alcohol, and high-risk human papillomavirus infection), and define the relationship between EBV and oral carcinomas.
Topics: Alcohol Drinking; Carcinoma, Squamous Cell; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Mouth Neoplasms; Smoking
PubMed: 32421990
DOI: 10.1615/CritRevOncog.2019031897 -
Genetics and Molecular Research : GMR Oct 2014The accuracy of prenatal diagnosis for abnormal chromosome diseases by chromosome microarray technology and karyotyping were compared. A literature search was carried... (Review)
Review
The accuracy of prenatal diagnosis for abnormal chromosome diseases by chromosome microarray technology and karyotyping were compared. A literature search was carried out in the MEDLINE database with the keywords "chromosome" and "karyotype" and "genetic testing" and "prenatal diagnosis" and "oligonucleotide array sequence". The studies obtained were filtered by using the QUADAS tool, and studies conforming to the quality standard were fully analyzed. There was one paper conforming to the QUADAS standards including 4406 gravidas with adaptability syndromes of prenatal diagnosis including elderly parturient women, abnormal structure by type-B ultrasound, and other abnormalities. Microarray technology yielded successful diagnoses in 4340 cases (98.8%), and there was no need for tissue culture in 87.9% of the samples. All aneuploids and non-parallel translocations in 4282 cases of non-chimera identified by karyotyping could be detected using microarray analysis technology, whereas parallel translocations and fetal triploids could not be detected by microarray analysis technology. In the samples with normal karyotyping results, type-B ultrasound showed that 6% of chromosomal deficiencies or chromosome duplications could be detected by microarray technology, and the same abnormal chromosomes were detected in 1.7% of elderly parturient women and samples with positive serology screening results. In the prenatal diagnosis test, compared with karyotyping, microarray technology could identify the extra cell genetic information with clinical significance, aneuploids, and non-parallel translocations; however, its disadvantage is that it could not identify parallel translocations and triploids.
Topics: Chromosome Disorders; Female; Fetal Diseases; Humans; Karyotyping; Microarray Analysis; Pregnancy; Prenatal Diagnosis; Reproducibility of Results; Sensitivity and Specificity
PubMed: 25366803
DOI: 10.4238/2014.October.31.27 -
Ultrasound in Obstetrics & Gynecology :... Apr 2018To establish, based on a systematic literature review, the frequency of pathogenic submicroscopic chromosomal aberrations in fetuses that are not at increased risk for... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To establish, based on a systematic literature review, the frequency of pathogenic submicroscopic chromosomal aberrations in fetuses that are not at increased risk for unbalanced structural chromosomal aberrations, with the aim of determining whether high-resolution testing for submicroscopic aberrations is beneficial in a general pregnant population.
METHODS
EMBASE, PubMed, Web of Science and CENTRAL databases were searched systematically on 3 June 2016 for all relevant articles on the prevalence of pathogenic submicroscopic copy number variants (CNVs) in fetuses referred for prenatal invasive testing because of advanced maternal age (AMA) or parental anxiety (ANX). Relevant full-text articles were analyzed and the prevalence of submicroscopic CNVs was calculated based on the extracted data. Meta-analysis was conducted in a pooled cohort of 10 614 fetuses based on the 10 largest studies (n > 300) of a total of 19 that were relevant.
RESULTS
Pooled estimate analysis indicated that 0.84% (95% CI, 0.55-1.30%) of fetuses that had invasive testing because of AMA/ANX carried a pathogenic clinically significant submicroscopic aberration. The onset/penetrance of submicroscopic findings was studied in 10 314 fetuses reported in eight papers that presented aberrant cases with all necessary details to allow assessment of the findings. The pooled estimates resulting from meta-analysis of the data indicated that an early-onset syndromic disorder was detected in 0.37% (95% CI, 0.27-0.52%) of cases, a susceptibility CNV was found in 0.30% (95% CI, 0.14-0.67%) and late-onset diseases were reported in 0.11% (95% CI, 0.05%-0.21%). The prevalence of early-onset syndromic disorders caused by a submicroscopic aberration was calculated to be 1:270. When the risk for submicroscopic aberrations is added to the individual risk for microscopic chromosomal aberrations, all pregnant women have a risk of higher than 1 in 180 for a relevant chromosomal aberration, and pregnant women under 36 years of age have a higher risk for submicroscopic pathogenic aberrations than for Down syndrome.
CONCLUSION
This systematic review shows that a significant proportion of fetuses in a general pregnant population carry a submicroscopic pathogenic CNV. Based on these figures, all women should be informed on their individual risk for all pathogenic chromosomal aberrations and not only for common trisomies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Chromosome Aberrations; Cohort Studies; DNA Copy Number Variations; Down Syndrome; Female; Humans; Maternal Age; Oligonucleotide Array Sequence Analysis; Pregnancy; Risk; Ultrasonography, Prenatal
PubMed: 28556491
DOI: 10.1002/uog.17533 -
Frontiers in Endocrinology 2021Molecular tests are being used increasingly as an auxiliary diagnostic tool so as to avoid a diagnostic surgery approach for cytologically indeterminate thyroid nodules... (Comparative Study)
Comparative Study Meta-Analysis
Thyroseq v3, Afirma GSC, and microRNA Panels Versus Previous Molecular Tests in the Preoperative Diagnosis of Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis.
BACKGROUND
Molecular tests are being used increasingly as an auxiliary diagnostic tool so as to avoid a diagnostic surgery approach for cytologically indeterminate thyroid nodules (ITNs). Previous test versions, Thyroseq v2 and Afirma Gene Expression Classifier (GEC), have proven shortcomings in malignancy detection performance.
OBJECTIVE
This study aimed to evaluate the diagnostic performance of the established Thyroseq v3, Afirma Gene Sequencing Classifier (GSC), and microRNA-based assays versus prior iterations in ITNs, in light of "rule-in" and "rule-out" concepts. It further analyzed the impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) reclassification and Bethesda cytological subtypes on the performance of molecular tests.
METHODS
Pubmed, Scopus, and Web of Science were the databases used for the present research, a process that lasted until September 2020. A random-effects bivariate model was used to estimate the summary sensitivity, specificity, positive (PLR) and negative likelihood ratios (NLR), and area under the curve (AUC) for each panel. The conducted sensitivity analyses addressed different Bethesda categories and NIFTP thresholds.
RESULTS
A total of 40 eligible studies were included with 7,831 ITNs from 7,565 patients. Thyroseq v3 showed the best overall performance (AUC 0.95; 95% confidence interval: 0.93-0.97), followed by Afirma GSC (AUC 0.90; 0.87-0.92) and Thyroseq v2 (AUC 0.88; 0.85-0.90). In terms of "rule-out" abilities Thyroseq v3 (NLR 0.02; 95%CI: 0.0-2.69) surpassed Afirma GEC (NLR 0.18; 95%CI: 0.10-0.33). Thyroseq v2 (PLR 3.5; 95%CI: 2.2-5.5) and Thyroseq v3 (PLR 2.8; 95%CI: 1.2-6.3) achieved superior "rule-in" properties compared to Afirma GSC (PLR 1.9; 95%CI: 1.3-2.8). Evidence for Thyroseq v3 seems to have higher quality, notwithstanding the paucity of studies. Both Afirma GEC and Thyroseq v2 performance have been affected by NIFTP reclassification. ThyGenNEXT/ThyraMIR and RosettaGX show prominent preliminary results.
CONCLUSION
The newly emerged tests, Thyroseq v3 and Afirma GSC, designed for a "rule-in" purpose, have been proved to outperform in abilities to rule out malignancy, thus surpassing previous tests no longer available, Thyroseq 2 and Afirma GEC. However, Thyroseq v2 still ranks as the best rule-in molecular test.
SYSTEMATIC REVIEW REGISTRATION
http://www.crd.york.ac.uk/PROSPERO, identifier CRD42020212531.
Topics: Area Under Curve; Biopsy, Fine-Needle; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; MicroRNAs; Oligonucleotide Array Sequence Analysis; Preoperative Period; Reproducibility of Results; Sensitivity and Specificity; Thyroid Neoplasms; Thyroid Nodule
PubMed: 34054725
DOI: 10.3389/fendo.2021.649522 -
Health Technology Assessment... Jun 2019Breast cancer and its treatment can have an impact on health-related quality of life and survival. Tumour profiling tests aim to identify whether or not women need...
BACKGROUND
Breast cancer and its treatment can have an impact on health-related quality of life and survival. Tumour profiling tests aim to identify whether or not women need chemotherapy owing to their risk of relapse.
OBJECTIVES
To conduct a systematic review of the effectiveness and cost-effectiveness of the tumour profiling tests onco DX (Genomic Health, Inc., Redwood City, CA, USA), MammaPrint (Agendia, Inc., Amsterdam, the Netherlands), Prosigna (NanoString Technologies, Inc., Seattle, WA, USA), EndoPredict (Myriad Genetics Ltd, London, UK) and immunohistochemistry 4 (IHC4). To develop a health economic model to assess the cost-effectiveness of these tests compared with clinical tools to guide the use of adjuvant chemotherapy in early-stage breast cancer from the perspective of the NHS and Personal Social Services.
DESIGN
A systematic review and health economic analysis were conducted.
REVIEW METHODS
The systematic review was partially an update of a 2013 review. Nine databases were searched in February 2017. The review included studies assessing clinical effectiveness in people with oestrogen receptor-positive, human epidermal growth factor receptor 2-negative, stage I or II cancer with zero to three positive lymph nodes. The economic analysis included a review of existing analyses and the development of a de novo model.
RESULTS
A total of 153 studies were identified. Only one completed randomised controlled trial (RCT) using a tumour profiling test in clinical practice was identified: Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) for MammaPrint. Other studies suggest that all the tests can provide information on the risk of relapse; however, results were more varied in lymph node-positive (LN+) patients than in lymph node-negative (LN0) patients. There is limited and varying evidence that onco DX and MammaPrint can predict benefit from chemotherapy. The net change in the percentage of patients with a chemotherapy recommendation or decision pre/post test ranged from an increase of 1% to a decrease of 23% among UK studies and a decrease of 0% to 64% across European studies. The health economic analysis suggests that the incremental cost-effectiveness ratios for the tests versus current practice are broadly favourable for the following scenarios: (1) onco DX, for the LN0 subgroup with a Nottingham Prognostic Index (NPI) of > 3.4 and the one to three positive lymph nodes (LN1-3) subgroup (if a predictive benefit is assumed); (2) IHC4 plus clinical factors (IHC4+C), for all patient subgroups; (3) Prosigna, for the LN0 subgroup with a NPI of > 3.4 and the LN1-3 subgroup; (4) EndoPredict Clinical, for the LN1-3 subgroup only; and (5) MammaPrint, for no subgroups.
LIMITATIONS
There was only one completed RCT using a tumour profiling test in clinical practice. Except for onco DX in the LN0 group with a NPI score of > 3.4 (clinical intermediate risk), evidence surrounding pre- and post-test chemotherapy probabilities is subject to considerable uncertainty. There is uncertainty regarding whether or not onco DX and MammaPrint are predictive of chemotherapy benefit. The MammaPrint analysis uses a different data source to the other four tests. The Translational substudy of the Arimidex, Tamoxifen, Alone or in Combination (TransATAC) study (used in the economic modelling) has a number of limitations.
CONCLUSIONS
The review suggests that all the tests can provide prognostic information on the risk of relapse; results were more varied in LN+ patients than in LN0 patients. There is limited and varying evidence that onco DX and MammaPrint are predictive of chemotherapy benefit. Health economic analyses indicate that some tests may have a favourable cost-effectiveness profile for certain patient subgroups; all estimates are subject to uncertainty. More evidence is needed on the prediction of chemotherapy benefit, long-term impacts and changes in UK pre-/post-chemotherapy decisions.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42017059561.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Breast Neoplasms; Chemotherapy, Adjuvant; Cost-Benefit Analysis; Female; Humans; Prognosis; Quality-Adjusted Life Years; Technology Assessment, Biomedical; Treatment Outcome
PubMed: 31264581
DOI: 10.3310/hta23300 -
Methods in Molecular Biology (Clifton,... 2014The outcome of Stage II melanoma is uncertain. Despite that 10-year melanoma-specific survival can approach 50 % following curative-intent wide local excision and... (Review)
Review
The outcome of Stage II melanoma is uncertain. Despite that 10-year melanoma-specific survival can approach 50 % following curative-intent wide local excision and negative sentinel lymph node biopsy, the adverse risk-benefit ratio of interferon-based adjuvant regimens precludes their use in most patients. The discovery and translation of protein-based prognostic biomarkers into the clinic offers the promise for residual risk stratification of Stage II melanoma patients beyond conventional clinicopathologic criteria to identify an additional subset of patients who, based upon tumor molecular profiles, might also derive benefit from adjuvant regimens. Despite incorporation of Ki-67 assays into clinical practice, systematic review of REMARK-compliant, immunostain-based prognostic biomarker assays in melanoma suggests that residual risk of recurrence might be best explained by a composite score derived from a small panel of proteins representing independent features of melanoma biology. Reflecting this trend, to date, five such multiparameter melanoma prognostic models have been published. Here, we review these five models and provide detailed protocols for discovering and validating multiparameter models including: appropriate cohort recruitment strategies, comprehensive laboratory protocols supporting fully quantitative chromogenic or fluorescent immunostaining platforms, statistical approaches to create composite prognostic indices recommended steps for model validation in independent cohorts.
Topics: Biomarkers, Tumor; Cohort Studies; Computational Biology; Humans; Melanoma; Models, Biological; Multivariate Analysis; Prognosis; Reproducibility of Results; Skin Neoplasms; Tissue Array Analysis; Treatment Outcome
PubMed: 24258982
DOI: 10.1007/978-1-62703-727-3_13 -
AJNR. American Journal of Neuroradiology Jun 2024Antibodies against leucine-rich glioma inactivated protein 1 (LGI1) constitute a common form of autoimmune encephalitis. On MR imaging, it may show T2 FLAIR...
BACKGROUND
Antibodies against leucine-rich glioma inactivated protein 1 (LGI1) constitute a common form of autoimmune encephalitis. On MR imaging, it may show T2 FLAIR hyperintensities of the medial temporal lobe (T2 FLAIR-MTL), involve the basal ganglia, or be unremarkable.
PURPOSE
We performed a systematic review and meta-analysis to obtain prevalence estimates of abnormal findings on MR imaging in anti-LGI1 encephalitis. A human brain map of the microarray gene expression was derived from the Allen Human Brain Atlas.
DATA SOURCES
PubMed and Web of Science were searched with the terms "LGI1" and "encephalitis" from inception to April 7, 2022.
STUDY SELECTION
Thirty-one research publications, encompassing case series and retrospective cohort and case-control studies, with >10 patients with anti-LGI1 encephalitis and MR imaging data were included.
DATA ANALYSIS
Pooled prevalence estimates were calculated using Freeman-Tukey double-arcsine transformation. Meta-analysis used DerSimonian and Laird random effects models.
DATA SYNTHESIS
Of 1318 patients in 30 studies, T2 FLAIR-MTL hyperintensities were present in 54% (95% CI, 0.48-0.60; I = 76%). Of 394 patients in 13 studies, 27% showed bilateral (95% CI, 0.19-0.36; I = 71%) and 24% unilateral T2 FLAIR-MTL abnormalities (95% CI, 0.17-0.32; I = 61%). Of 612 patients in 15 studies, basal ganglia abnormalities were present in 10% (95% CI, 0.06-0.15; I = 67%). expression was highest in the amygdala, hippocampus, and caudate nucleus.
LIMITATIONS
Only part of the spectrum of MR imaging abnormalities in anti-LGI1 encephalitis could be included in a meta-analysis. MR imaging findings were not the main outcomes in most studies, limiting available information. I values ranged from 62% to 76%, representing moderate-to-large heterogeneity.
CONCLUSIONS
T2 FLAIR-MTL hyperintensities were present in around one-half of patients with anti-LGI1. The prevalence of unilateral and bilateral presentations was similar, suggesting unilaterality should raise the suspicion of this disease in the appropriate clinical context. Around 10% of patients showed basal ganglia abnormalities, indicating that special attention should be given to this region. regional expression coincided with the most frequently reported abnormal findings on MR imaging. Regional specificity might be partially determined by expression levels of the target protein.
PubMed: 38871367
DOI: 10.3174/ajnr.A8256 -
Pregnancy Hypertension Jan 2020Preeclampsia (PE) is a serious complication of pregnancy. It is considered a complex condition influenced by maternal genes, environmental factors and a deregulated... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Preeclampsia (PE) is a serious complication of pregnancy. It is considered a complex condition influenced by maternal genes, environmental factors and a deregulated immune response of the mother, but the etiology is largely unknown. The aim of this study is to identify differentially expressed genes (DEGs) in PE, to help elucidate the identification of the disease etiological mechanisms.
STUDY DESIGN
The databases Pubmed and GEO were searched according to PRISMA guidelines for the existence of gene expression data on placental samples from case-control studies. After meta-analysis the identified DEGs were further analyzed with STRING and PANTHER to retrieve interaction networks and overrepresented biochemical pathways.
RESULTS
Only 10 gene expression datasets and articles fulfilled inclusion criteria, containing data on 195 patients and 231 controls, and were analyzed. Meta-analysis identified 629 DEGs to be associated with PE at a False Discovery Rate p-value of 0.01. Network analysis showed few highly interconnected genes involved in innate immunity and signal transduction pathways indicative of a multifaceted disease with etiological heterogeneity. over representation analysis revealed that these genes participate mainly in carbohydrates, amino acids and pyrimidine metabolism, circadian clock system and signal transduction pathways.
CONCLUSIONS
This work, combining rigorous methods of meta-analysis and the use of modern bioinformatics tools, proposes the existence of novel, overlooked so far, biochemical pathways and mechanisms to contribute to PE development such as carbohydrate, aminoacids and pyrimidine metabolism. Our findings pave the way for further investigation of the above pathways in experimental efforts to decipher the orchestrating mechanisms for PE development.
Topics: Female; Gene Expression Profiling; Humans; Microarray Analysis; Pre-Eclampsia; Pregnancy
PubMed: 31901653
DOI: 10.1016/j.preghy.2019.12.007