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The Lancet. Digital Health Jan 2023One challenge in the field of in-vitro fertilisation is the selection of the most viable embryos for transfer. Morphological quality assessment and morphokinetic...
BACKGROUND
One challenge in the field of in-vitro fertilisation is the selection of the most viable embryos for transfer. Morphological quality assessment and morphokinetic analysis both have the disadvantage of intra-observer and inter-observer variability. A third method, preimplantation genetic testing for aneuploidy (PGT-A), has limitations too, including its invasiveness and cost. We hypothesised that differences in aneuploid and euploid embryos that allow for model-based classification are reflected in morphology, morphokinetics, and associated clinical information.
METHODS
In this retrospective study, we used machine-learning and deep-learning approaches to develop STORK-A, a non-invasive and automated method of embryo evaluation that uses artificial intelligence to predict embryo ploidy status. Our method used a dataset of 10 378 embryos that consisted of static images captured at 110 h after intracytoplasmic sperm injection, morphokinetic parameters, blastocyst morphological assessments, maternal age, and ploidy status. Independent and external datasets, Weill Cornell Medicine EmbryoScope+ (WCM-ES+; Weill Cornell Medicine Center of Reproductive Medicine, NY, USA) and IVI Valencia (IVI Valencia, Health Research Institute la Fe, Valencia, Spain) were used to test the generalisability of STORK-A and were compared measuring accuracy and area under the receiver operating characteristic curve (AUC).
FINDINGS
Analysis and model development included the use of 10 378 embryos, all with PGT-A results, from 1385 patients (maternal age range 21-48 years; mean age 36·98 years [SD 4·62]). STORK-A predicted aneuploid versus euploid embryos with an accuracy of 69·3% (95% CI 66·9-71·5; AUC 0·761; positive predictive value [PPV] 76·1%; negative predictive value [NPV] 62·1%) when using images, maternal age, morphokinetics, and blastocyst score. A second classification task trained to predict complex aneuploidy versus euploidy and single aneuploidy produced an accuracy of 74·0% (95% CI 71·7-76·1; AUC 0·760; PPV 54·9%; NPV 87·6%) using an image, maternal age, morphokinetic parameters, and blastocyst grade. A third classification task trained to predict complex aneuploidy versus euploidy had an accuracy of 77·6% (95% CI 75·0-80·0; AUC 0·847; PPV 76·7%; NPV 78·0%). STORK-A reported accuracies of 63·4% (AUC 0·702) on the WCM-ES+ dataset and 65·7% (AUC 0·715) on the IVI Valencia dataset, when using an image, maternal age, and morphokinetic parameters, similar to the STORK-A test dataset accuracy of 67·8% (AUC 0·737), showing generalisability.
INTERPRETATION
As a proof of concept, STORK-A shows an ability to predict embryo ploidy in a non-invasive manner and shows future potential as a standardised supplementation to traditional methods of embryo selection and prioritisation for implantation or recommendation for PGT-A.
FUNDING
US National Institutes of Health.
Topics: United States; Pregnancy; Female; Humans; Male; Young Adult; Adult; Middle Aged; Retrospective Studies; Artificial Intelligence; Preimplantation Diagnosis; Semen; Ploidies; Blastocyst; Aneuploidy
PubMed: 36543475
DOI: 10.1016/S2589-7500(22)00213-8 -
Current Biology : CB May 2015Polyploidy is defined as an increase in genome DNA content. Throughout the plant and animal kingdoms specific cell types become polyploid as part of their...
Polyploidy is defined as an increase in genome DNA content. Throughout the plant and animal kingdoms specific cell types become polyploid as part of their differentiation programs. When this occurs in subsets of tissues within an organism it is termed somatic polyploidy, because it is distinct from the increase in ploidy that is inherited through the germline and present in every cell type of the organism. Germline polyploidy is common in plants and occurs in some animals, such as amphibians, but will not be discussed further here. Somatic polyploid cells can be mononucleate or multinucleate, and the replicated sister chromatids can remain attached and aligned, producing polytene chromosomes, or they can be dispersed (Figure 1). In this Primer, we focus on why somatic polyploidy occurs and how cells become polyploid — the first of these issues being more speculative, given the status of the field.
Topics: Cell Cycle; Cell Size; DNA Replication; Gene Expression; Polyploidy
PubMed: 25942544
DOI: 10.1016/j.cub.2015.03.037 -
Trends in Genetics : TIG Sep 2017Unreduced gametes, which have the somatic (2n) chromosome number, are an important precursor to polyploid formation and apomixis. The product of irregularities in... (Review)
Review
Unreduced gametes, which have the somatic (2n) chromosome number, are an important precursor to polyploid formation and apomixis. The product of irregularities in meiosis, 2n gametes are expected to be rare and deleterious in most natural populations, contrary to their wide taxonomic distribution and the prevalence of polyploidy. To better understand this discrepancy, we review contemporary evidence related to four aspects of 2n gamete dynamics in natural populations: (i) estimates of their frequency; (ii) their environmental and genetic determinants; (iii) adaptive and nonadaptive processes regulating their evolution; and (iv) factors regulating their union and production of polyploids in diploid populations. Aided by high-throughput methods of detection, these foci will advance our understanding of variation in 2n gametes within and among species, and their role in polyploid evolution.
Topics: Evolution, Molecular; Germ Cells; Ploidies
PubMed: 28732599
DOI: 10.1016/j.tig.2017.06.009 -
Journal of Clinical Oncology : Official... Mar 2017Multiple myeloma (MM) is characterized by wide variability in the chromosomal/genetic changes present in tumor plasma cells. Genetically, MM can be divided into two... (Review)
Review
Multiple myeloma (MM) is characterized by wide variability in the chromosomal/genetic changes present in tumor plasma cells. Genetically, MM can be divided into two groups according to ploidy and hyperdiploidy versus nonhyperdiploidy. Several studies in gene expression profiling attempted to identify subentities in MM without convincing results. These studies mostly confirmed the cytogenetic data and subclassified patients according to 14q32 translocations and ploidy. More-recent data that are based on whole-exome sequencing have confirmed this heterogeneity and show many gene mutations but without a unifying mutation. These newer studies have shown the frequent alteration of the mitogen-activated protein kinase pathway. The most interesting data have demonstrated subclonality in all patients with MM, including subclonal mutations of supposed driver genes KRAS, NRAS, and BRAF.
Topics: Genomics; High-Throughput Nucleotide Sequencing; Humans; Multiple Myeloma; Mutation; Ploidies
PubMed: 28297630
DOI: 10.1200/JCO.2016.70.6705 -
Cells Jun 2023The adult heart is made up of cardiomyocytes (CMs) that maintain pump function but are unable to divide and form new myocytes in response to myocardial injury. In... (Review)
Review
The adult heart is made up of cardiomyocytes (CMs) that maintain pump function but are unable to divide and form new myocytes in response to myocardial injury. In contrast, the developmental cardiac tissue is made up of proliferative CMs that regenerate injured myocardium. , CMs during development are diploid and mononucleated. In response to cardiac maturation, CMs undergo polyploidization and binucleation associated with CM functional changes. The transition from mononucleation to binucleation coincides with unique metabolic changes and shift in energy generation. Recent studies provide evidence that metabolic reprogramming promotes CM cell cycle reentry and changes in ploidy and nucleation state in the heart that together enhances cardiac structure and function after injury. This review summarizes current literature regarding changes in CM ploidy and nucleation during development, maturation and in response to cardiac injury. Importantly, how metabolism affects CM fate transition between mononucleation and binucleation and its impact on cell cycle progression, proliferation and ability to regenerate the heart will be discussed.
Topics: Animals; Adult; Humans; Myocytes, Cardiac; Myocardium; Ploidies; Heart Injuries; Cell Cycle; Mammals
PubMed: 37371041
DOI: 10.3390/cells12121571 -
Nature Reviews. Gastroenterology &... Nov 2018
Topics: Animals; Cell Proliferation; Hepatocytes; Liver Regeneration; Mice; Ploidies; Polyploidy
PubMed: 30323318
DOI: 10.1038/s41575-018-0076-8 -
Development (Cambridge, England) Aug 2023Developmentally programmed polyploidy (whole-genome duplication) of cardiomyocytes is common across evolution. Functions of such polyploidy are essentially unknown....
Developmentally programmed polyploidy (whole-genome duplication) of cardiomyocytes is common across evolution. Functions of such polyploidy are essentially unknown. Here, in both Drosophila larvae and human organ donors, we reveal distinct polyploidy levels in cardiac organ chambers. In Drosophila, differential growth and cell cycle signal sensitivity leads the heart chamber to reach a higher ploidy/cell size relative to the aorta chamber. Cardiac ploidy-reduced animals exhibit reduced heart chamber size, stroke volume and cardiac output, and acceleration of circulating hemocytes. These Drosophila phenotypes mimic human cardiomyopathies. Our results identify productive and likely conserved roles for polyploidy in cardiac chambers and suggest that precise ploidy levels sculpt many developing tissues. These findings of productive cardiomyocyte polyploidy impact efforts to block developmental polyploidy to improve heart injury recovery.
Topics: Animals; Humans; Drosophila; Myocytes, Cardiac; Polyploidy; Ploidies; Cell Cycle
PubMed: 37526609
DOI: 10.1242/dev.201896 -
Bioinformatics (Oxford, England) Jul 2023The resemble between relatives computed from pedigree and genomic data is an important resource for geneticists and ecologists, who are interested in understanding how...
MOTIVATION
The resemble between relatives computed from pedigree and genomic data is an important resource for geneticists and ecologists, who are interested in understanding how genes influence phenotypic variation, fitness adaptation, and population dynamics.
RESULTS
The AGHmatrix software is an R package focused on the construction of pedigree (A matrix) and/or molecular markers (G matrix), with the possibility of building a combined matrix of pedigree corrected by molecular markers (H matrix). Designed to estimate the relationships for any ploidy level, the software also includes auxiliary functions related to filtering molecular markers, and checks pedigree errors in large data sets. After computing the relationship matrices, results from the AGHmatrix can be used in different contexts, including on prediction of (genomic) estimated breeding values and genome-wide association studies.
AVAILABILITY AND IMPLEMENTATION
AGHmatrix v2.1.0 is available under GPL-3 license in CRAN at https://cran.r-project.org/web/packages/AGHmatrix/index.html and also in GitHub at https://github.com/rramadeu/AGHmatrix. It has a comprehensive tutorial, and it follows with real data examples.
Topics: Genome-Wide Association Study; Software; Genomics; Ploidies; Pedigree
PubMed: 37471595
DOI: 10.1093/bioinformatics/btad445 -
Philosophical Transactions of the Royal... Dec 2016Rapid responses to acute stresses are essential for stress survival and are critical to the ability of fungal pathogens to adapt to new environments or hosts. The rapid... (Review)
Review
Rapid responses to acute stresses are essential for stress survival and are critical to the ability of fungal pathogens to adapt to new environments or hosts. The rapid emergence of drug resistance is used as a model for how fungi adapt and survive stress conditions that inhibit the growth of progenitor cells. Aneuploidy and loss of heterozygosity (LOH), which are large-scale genome shifts involving whole chromosomes or chromosome arms, occur at higher frequency than point mutations and have the potential to mediate stress survival. Furthermore, the stress of exposure to an antifungal drug can induce elevated levels of LOH and can promote the formation of aneuploids. This occurs via mitotic defects that first produce tetraploid progeny with extra spindles, followed by chromosome mis-segregation. Thus, drug exposure induces elevated levels of aneuploidy, which can alter the copy number of genes that improve survival in a given stress or drug. Selection then acts to increase the proportion of adaptive aneuploids in the population. Because aneuploidy is a common property of many pathogenic fungi, including those posing emerging threats to plants, animals and humans, we propose that aneuploid formation and LOH often accompanying it contribute to the rapid generation of diversity that can facilitate the emergence of fungal pathogens to new environmental niches and/or new hosts, as well as promote antifungal drug resistance that makes emerging fungal infections ever more difficult to contain.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'.
Topics: Aneuploidy; Antifungal Agents; Biological Evolution; Drug Resistance, Fungal; Evolution, Molecular; Fungi; Phenotype; Ploidies
PubMed: 28080987
DOI: 10.1098/rstb.2015.0461 -
Biochimica Et Biophysica Acta. Reviews... Sep 2022Aberrant ploidy status is a prominent characteristic in malignant neoplasms. Approximately 90% of solid tumors and 75% of haematopoietic malignancies contain aneuploidy... (Review)
Review
Aberrant ploidy status is a prominent characteristic in malignant neoplasms. Approximately 90% of solid tumors and 75% of haematopoietic malignancies contain aneuploidy cells, and 30%-60% of tumors undergo whole-genome doubling, indicating that nondiploidy might be a prevalent genomic aberration in cancer. Although the role of aneuploid and polyploid cells in cancer remains to be elucidated, recent studies have suggested that nondiploid cells might be a dangerous minority that severely challenges cancer management. Ploidy shifts cause multiple fitness coasts for cancer cells, mainly including genomic, proteotoxic, metabolic and immune stresses. However, nondiploid comprises a well-adopted subpopulation, with many tolerance mechanisms evident in cells along with ploidy shifts. Aneuploid and polyploid cells elegantly maintain an autonomous balance between the stress and tolerance during adaptive evolution in cancer. Breaking the balance might provide some inspiration for ploidy-selective cancer therapy and alleviation of ploidy-related chemoresistance. To understand of the complex role and therapeutic potential of nondiploid cells better, we reviewed the survival stresses and adaptive tolerances within nondiploid cancer cells and summarized therapeutic ploidy-selective alterations for potential use in developing future cancer therapy.
Topics: Aneuploidy; Humans; Neoplasms; Ploidies; Polyploidy
PubMed: 36075287
DOI: 10.1016/j.bbcan.2022.188794