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PubMed2025

Accurate identification of abnormal ploidy using an artificial intelligence model in preimplantation genetic testing.

STUDY QUESTION: Can ultra-low-coverage whole-genome sequencing (ulc-WGS) accurately identify abnormal ploidy during preimplantation genetic testing (PGT)? SUMMARY ANSWER: The artificial intelligence (AI)-based PGT-Plus model demonstrates high accuracy in ploidy detection, offering a cost-effective solution that enhances clinical utility of PGT. WHAT IS KNOWN ALREADY: The predominant PGT for aneuploidy can identify chromosomal aneuploidies but cannot determine ploidy status. Transferring embryos with ploidy abnormalities can result in miscarriage and molar pregnancy. On the other hand, in ART, fertilization is assessed by morphological pronuclear assessment at the zygote stage. However, it has a low specificity in the prediction of abnormal ploidy status and embryos deemed abnormally fertilized can yield healthy pregnancies. Accurately identified abnormal ploidy in PGT-A can resolve current limitations and expand the utility range of PGT-A. Several studies have identified ploidy abnormalities; however, they were mainly based on single-nucleotide polymorphism (SNP) arrays or needed to combine additional targeted-next-generation sequencing (NGS) information. Studies based on ulc-WGS remain scarce. STUDY DESIGN SIZE DURATION: The study consisted of two stages: methodology establishment and validation. An AI model, named PGT-Plus, was developed using 653 samples with known ploidy status, which was further validated using 792 different ploidy status samples. In the clinical application stage, the approach was used to analyse the ploidy status of 19 103 normally fertilized PGT blastocysts and 140 single pronucleus (1PN)-derived blastocysts collected between May 2022 and December 2023. All blastocysts were tested using trophectoderm biopsy and NGS. PARTICIPANTS/MATERIALS SETTING METHODS: The methodology is based on the ulc-WGS data. First, based on samples with known ploidy status: the heterozygosity rate of high-frequency biallelic SNPs, the likelihood ratio (LLR) of alleles was calculated under different assumptions ('both parental homologs' [BPH] from a single parent, 'single parental homolog' [SPH] from each parent, disomy, and monosomy) by leveraging allele frequencies and linkage disequilibrium (LD) measured in the 1000 genomes project database. Twenty-three continuous candidate features derived from heterozygosity rates and LLRs of chromosomes or selected windows were included to establish the ploidy prediction AI model. Gini importance analysis and multicollinearity mitigation was performed for feature selection, then the performance of Random Forest (RF), Support Vector Machine (SVM), and Logistic Regression for modelling was compared. Subsequently, the parameter optimization was performed based on the RF model. Ploidy constitution concordance was evaluated in known ploidy status samples. The frequency of abnormal ploidy in normal fertilized PGT blastocysts and 1PN-derived blastocysts (including conventional IVF and ICSI) was evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Eleven features were collected for model architecture compared to SVM and Logistic Regression; RF achieved superior performance for ploidy detection. The AI model achieved an AUC of 1 for genome-wide-uniparental diploidy (GW-UPD), 1 for triploidy, and 0.99 for diploidy. For the 792 validation samples, 99.5% of samples were successfully detected using the AI model, and the model showed 100% accuracy for ploidy classification. In the clinical application stage, out of 19 103 PGT samples, 19 069 were successfully analysed using the model, with 110 (0.57%) identified as having abnormal ploidy embryos. Among these, 12.7% (14/110) were identified as GW-UPD, and 87.3% (96/110) were triploid. Among 5563 diploid blastocysts transferred, 3478 clinical pregnancies were achieved. Subsequent ploidy analysis was performed for 217 spontaneous abortion and 935 prenatal diagnostic samples, and no abnormal ploidy was identified. Furthermore, of the 140 1PN embryos tested, 40 (28.6%) exhibited GW-UPD, 3 (2.1%) exhibited triploidy, and 97 (69.3%) were determined to be biparental and normally fertilized. Among the 97 biparental embryos, 46 were diploid, 11 were mosaic, and 40 were aneuploid. In terms of the insemination pattern, the percentage of abnormal ploidy in ICSI was significantly higher than in conventional IVF (P < 0.01, 37.1% vs. 2.9%, respectively). With full informed consent, 20 patients without euploidy from normal fertilization chose 1PN-derived biparental and diploid blastocysts to transfer, resulting in 10 clinical pregnancies and 9 ongoing pregnancies. LARGE-SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: Some rare ploidy abnormalities, such as polyploidy with an equal number of identical sets of chromosomes and ploidy mosaicism cannot be accurately identified. Moreover, the origin of abnormal ploidy was not identified due to the unavailability of DNA from both parents. WIDER IMPLICATIONS OF THE FINDINGS: The PGT-Plus AI model provides a ploidy evaluation method based on the conventional PGT-A data and integrates directly into standard PGT-A workflows. Clinical utility results suggest that the model is a valuable tool for identifying embryos with abnormal ploidy in PGT-A and rescuing normal diploid embryos from abnormally fertilized embryos. These findings demonstrate that PGT-Plus significantly enhances the diagnostic accuracy of PGT. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from Major Scientific Program of CITIC Group (No. 2023ZXKYB34100, to Ge.L.), Hunan Provincial Grant for Innovative Province Construction (2019SK4012), Hunan Xiangjiang New District (Changsha High-tech Zone) key core technology research project in 2023, and Science Foundation of Hunan Province (Grant 2023JJ30422). All authors declared no conflicts of interest..

artificial intelligence↗

PubMed2003

Electroporation, an alternative to biolistics for transfection of Bombyx mori embryos and larval tissues.

There are few powerful techniques available to transfect insect tissues. We previously used biolistics to transfect Bombyx mori embryos, and larval and pupal tissues (Thomas J-L et al. 2001. Journal of Insect Science 1/9, Kravariti L et al. 2001. Insect Biochemistry and Molecular Biology 31: 473-479). As the main limitation was the irregularity in results we explored electroporation as an alternative technique by adapting techniques used for chicken embryos to B. mori embryos. By injecting the DNA solution into the hemocoel of late embryos that were finishing organogenesis, we expressed marker genes in numerous tissues following electroporation. With some adaptation of the method this was also achieved for early embryos lacking a hemocoel. Some larval tissues were also transfected. During these technical studies we found that optimizing parameters such as electrical voltage, number of pulses and their frequency, and conductivity of the buffer was important. These results confirmed that electroporation is a reliable technique for transfecting B. mori tissues.

Animals↗

PubMed1991

Neural network optimization for E. coli promoter prediction.

Methods for optimizing the prediction of Escherichia coli RNA polymerase promoter sequences by neural networks are presented. A neural network was trained on a set of 80 known promoter sequences combined with different numbers of random sequences. The conserved -10 region and -35 region of the promoter sequences and a combination of these regions were used in three independent training sets. The prediction accuracy of the resulting weight matrix was tested against a separate set of 30 known promoter sequences and 1500 random sequences. The effects of the network's topology, the extent of training, the number of random sequences in the training set and the effects of different data representations were examined and optimized. Accuracies of 100% on the promoter test set and 98.4% on the random test set were achieved with the optimal parameters.

Artificial Intelligence↗

PubMed1997

Chemical synthesis and characterization of branched oligodeoxyribonucleotides (bDNA) for use as signal amplifiers in nucleic acid quantification assays.

The divergent synthesis of bDNA structures is described. This new type of branched DNA contains one unique oligonucleotide, the primary sequence, covalently attached through a comb-like branching network to many identical copies of a different oligonucleotide, the secondary sequence. The bDNA comb molecules were assembled on a solid support using parameters optimized for bDNA synthesis. The chemistry was used to synthesize bDNA comb molecules containing 15 secondary sequences. The bDNA comb molecules were elaborated by enzymatic ligation into branched amplification multimers, large bDNA molecules (a total of 1068 nt) containing an average of 36 repeated DNA oligomer sequences, each capable of hybridizing specifically to an alkaline phosphatase-labeled oligonucleotide. The bDNA comb molecules were characterized by electrophoretic methods and by controlled cleavage at periodate-cleavable moieties incorporated during synthesis. The branched amplification multimers have been used as signal amplifiers in nucleic acid quantification assays for detection of viral infection. It is possible to detect as few as 50 molecules with bDNA technology.

DNA↗

PubMed2002

Use of covariance analysis for the prediction of structural domain boundaries from multiple protein sequence alignments.

Current methods for identification of domains within protein sequences require either structural information or the identification of homologous domain sequences in different sequence contexts. Knowledge of structural domain boundaries is important for fold recognition experiments and structural determination by X-ray crystallography or nuclear magnetic resonance spectroscopy using the divide-and-conquer approach. Here, a new and conceptually simple method for the identification of structural domain boundaries in multiple protein sequence alignments is presented. Analysis of covariance at positions within the alignment is first used to predict 3D contacts. By the nature of the domain as an independent folding unit, inter-domain predicted contacts are fewer than intra-domain predicted contacts. By analysing all possible domain boundaries and constructing a smoothed profile of predicted contact density (PCD), true structural domain boundaries are predicted as local profile minima associated with low PCD. A training data set is constructed from 52 non-homologous two-domain protein sequences of known 3D structure and used to determine optimal parameters for the profile analysis. The alignments in the training data set contained 48 +/- 17 (mean +/- SD) sequences and lengths of 257 +/- 121 residues. Of the 47 alignments yielding predictions, 35% of true domain boundaries are predicted to within 15 amino acids by the local profile minimum with the lowest profile value. Including predictions from the second- and third-lowest local minima increases the correct domain boundary coverage to 60%, whereas the lowest five local minima cover 79% of correct domain boundaries. Through further profile analysis, criteria are presented which reliably identify subsets of more accurate predictions. Retrospective analysis of CASP3 targets shows predictions of sufficient accuracy to enable dramatically improved fold recognition results. Finally, a prediction is made for geminivirus AL1 protein which is in full agreement with biochemical data, yielding a plausible, novel threading result.

DNA-Binding Proteins↗

PubMed1993

Direct evidence for the synaptic resonance phenomenon.

Via the parameter optimization method, well documented in the literature, data on the facilitated release of acetylcholine from the preganglionic nerve terminals during short trains of impulses have been quantitatively generalized within the framework of the previously developed theory of the double barrier synapse. This allowed unique transformation of the set of discrete measurements of facilitated transmitter release into continuous dependencies of facilitation on time and frequency and, subsequently, into the resonant curves having very readily interpreted computational meaning. Thus direct evidence is produced that an overall effect of facilitory action of presynaptic stimulation does indeed reflect resonant properties of the terminal in a form of the previously predicted synaptic resonance phenomenon.

Acetylcholine↗

PubMedDate not supplied

Cerebrovascular enhancement in spoiled GRASS (SPGR) images: comparison with spin-echo technique.

The signals and artifacts in cerebral blood vessels were systematically studied using a new three-dimensional Fourier transform (3DFT) technique, spoiled gradient recalled acquisition in steady state (SPGR), with parameters optimized for T1-weighted brain imaging. Twenty consecutive patients referred for routine cranial MR imaging were prospectively studied before and after the intravenous administration of Gd-DTPA using both 3DFT SPGR and conventional 2DFT SE imaging. A significant difference between the two techniques was noted in regard to the appearance of cerebral blood vessels and the degree of vascular pulsation artifact. Precontrast SPGR images demonstrated high signal in all (100%) internal carotid arteries and in nearly all (85-95%) vertebral, basilar, and proximal posterior, middle, and anterior cerebral arteries. High signal was variably present (5-50%) in more distal arterial branches. High signal from venous structures was not seen except in the superior sagittal sinus, which was bright in 75% of cases. Postcontrast SPGR images reliably demonstrated uniform high signal in all (100%) major arterial branches, up to fourth-order branches in the middle cerebral artery, diminishing toward the vertex. All (100%) major deep and superficial venous structures were of uniformly high signal, diminishing slightly as they exited the skull base. Flow related artifacts were found to be significantly (p = 0.001) reduced in contrast enhanced SPGR compared to SE images. As implemented in this study, SPGR and SE images demonstrate significantly different patterns of vascular signal that must be recognized for the proper interpretation of MR images.

Adolescent↗

PubMed2001

Exercise training in heart failure: recommendations based on current research.

A review of methods used for exercise training in stable chronic heart failure patients (CHF) shows a lack of standardization to guide prescription. Previous recommendations have been adopted from fitness training or rehabilitation studies. A model for use in CHF patients requires specific guidelines which respect the various manifestations of this illness. Pathology and exercise tolerance of patients with CHF allow only a few selected activities to be performed, such as walking and cycle ergometer training. Although the steady state method has usually been applied for aerobic exercise, the interval method has been shown to cause greater exercise stimuli to peripheral muscle than that obtained during steady state training methods without inducing greater cardiovascular stress. There is no consensus at present as to an optimal parameter for measuring intensity. An intensity of 40-80% peak oxygen consumption (VO(2)) has been applied successfully. A heart rate reserve of 60-80% or 75% of peak heart rate was used as a guide to exercise intensity without consideration of the impaired force-frequency relationship in myocardial performance. Because intensity, duration, and frequency of exercise are closely interrelated, initial exercise should be kept at 40-50% peak VO(2) with exercise duration of > 3-5 min x session performed several times daily. Progression should be followed in this order: duration, then frequency, then intensity. Resistance training can be recommended when small muscle groups are involved, using short bouts of work phases and small numbers of repetitions. To increase respiratory muscle strength and endurance, resistive inspiratory muscle training at intensity 25--35% maximum inspiratory pressure, and performed 20-30 min x d(-1), is recommended. On the basis of currently available research, supervised inpatient training programs should be preferred. Future research should be performed with respect on statistically sufficient, randomized, and controlled long-term studies that compare different training modes, intensities, frequency/duration ratios, and rates of progression.

Exercise Therapy↗

PubMed1997

Long-term precision of glomerular filtration rate measurements using 51Cr-EDTA plasma clearance.

The long-term precision of chromium-51 ethylenediamine tetraacetic acid (51Cr-EDTA) measurements of glomerular filtration rate (GFR) was evaluated in a retrospective study of data obtained over a 12 year period. Each GFR measurement was derived from plasma samples taken at 2, 3 and 4 h following injection of 3 MBq 51Cr-EDTA. The records of 7507 patients were reviewed, from which 55 subjects were identified as having had studies on 10 or more occasions. The mean number of studies per patient was 12.9 (range 10-23) over a mean period of 9.4 years (range 4.3-11.8 years). Plots of GFR, clearance half-life, (T1/2) and volume of distribution (VD) were drawn for each patient and used to identify subjects showing linear changes with time that could be fitted using linear regression. Each residual was expressed as a percentage of the expected value calculated from the regression line and all the residuals combined to give histograms for GFR, T1/2 and VD. Each histogram was fitted with a normal distribution between the -3 S.D. and +3 S.D. limits using weighted least squares. Final results for the coefficient of variation were: GFR 9.8%, T1/2 6.7%, VD 9.4%. The precision errors were used to calculate the smallest statistically significant change measurable by the 51Cr-EDTA technique. With 10% significance and 80% power, the smallest measureable change was 30% for GFR and 20% for T1/2. Unless there are clinical grounds for thinking that a patient's volume of distribution has changed, T1/2 is the optimal parameter for identifying real changes in renal function.

Chromium Radioisotopes↗

PubMed1993

Diffractive bifocal lens designs.

Modifying the number, width, depth, and shape of the echelettes in a diffractive bifocal lens will influence the image intensity and quality within the zero, first, and higher order images. By appropriately varying these parameters optimal bifocal lens designs may be achieved.

Contact Lenses↗

PubMed1998

Multivariate analysis of factors influencing repeat expansion detection.

Repeat expansion detection (RED) is a powerful tool for detection of expanded repeat sequences in the genome. In RED, DNA serves as a template for a repeat-specific oligonucleotide. A thermostable ligase is used to ligate oligonucleotides that have annealed at adjacent positions, creating multimers in a thermal cycling procedure. The products are visualized after gel electrophoresis, transfered to a membrane and subsequently hybridized. Multiple linear regression (MLR) and partial least square (PLS) techniques were used to reveal the most influential factors in the amplification reaction and to identify possible interacting factors. Ligation temperature proved to be the most important factor in the reaction: Temperatures far below the melting point of the oligonucleotide increased the yield considerably. Higher cycle number resulted in a continuous rise in intensity, indicating that the ligase remained active even after 700 cycles or 12 hr of cycling. In addition, the concentration of ligase was found to be important. Using optimal parameters, a 5.5- and 3.2-fold increase in the yield of 180- and 360-nucleotide products respectively was obtained. The improved sensitivity makes the method more robust and facilitates detection of repeat expansions. This improvement may be particularly useful in development of RED for diagnostic purposes as well as for nonradioactive detection of RED products. Based on these results, a new protocol for the RED method was developed taking into account the risk of introducing artifacts with increased enzyme concentrations and lowered annealing temperatures.

DNA↗

PubMed2000

Shock compression of condensed matter using intense beams of energetic heavy ions

In this paper is presented, with the help of sophisticated two-dimensional hydrodynamic simulations, a suitable design with optimized parameters for a heavy-ion beam-matter interaction experiment that will be carried out at the Gesellschaft fur Schwerionenforschung (GSI) Darmstadt by the end of the year 2001 when the upgrade of the existing accelerator facility will be completed. Our simulations show that this upgraded heavy-ion beam is capable of generating strong shocks in solid targets that compress the target material to supersolid densities and generate multi-mbar pressures. This will open up, at the GSI, the possibility of investigation of the equation-of-state properties of matter under such extreme conditions. Numerical simulations can predict the experimental results with reasonable accuracy, which is helpful in designing the diagnostic tools for the experiment.

Journal Article↗

PubMed2002

Analytical properties and optimization of time-delayed feedback control.

Time-delayed feedback control is an efficient method for stabilizing unstable periodic orbits of chaotic systems. If the equations governing the system dynamics are known, the success of the method can be predicted by a linear stability analysis of the desired orbit. Unfortunately, the usual procedures for evaluating the Floquet exponents of such systems are rather intricate. We show that the main stability properties of the system controlled by time-delayed feedback can be simply derived from a leading Floquet exponent defining the system behavior under proportional feedback control. Optimal parameters of the delayed feedback controller can be evaluated without an explicit integration of delay-differential equations. The method is valid for low-dimensional systems whose unstable periodic orbits are originated from a period doubling bifurcation and is demonstrated for the Rössler system and the Duffing oscillator.

Journal Article↗

PubMed2002

Etched distributed Bragg reflectors as three-dimensional photonic crystals: photonic bands and density of states.

The photonic band dispersion and density of states (DOS) are calculated for the three-dimensional (3D) hexagonal structure corresponding to a distributed Bragg reflector patterned with a 2D triangular lattice of circular holes. Results for the Si/SiO(2) and GaAs/Al(x)Ga(1-x)As systems determine the optimal parameters for which a gap in the 2D plane occurs and overlaps the 1D gap of the multilayer. The DOS is considerably reduced in correspondence with the overlap of 2D and 1D gaps. Also, the local density of states (i.e., the DOS weighted with the squared electric field at a given point) has strong variations depending on the position. Both results imply substantial changes of spontaneous emission rates and patterns for a local emitter embedded in the structure and make this system attractive for the fabrication of a 3D photonic crystal with controlled radiative properties.

Journal Article↗

PubMed2006

Single-polymer Brownian motor: a simulation study.

Numerical simulation is used to study a single polymer chain in a flashing ratchet potential to determine how the mechanism of this Brownian motor system is affected by the presence of internal degrees of freedom. The polymer is modeled by a freely jointed chain with N monomers in which the monomers interact via a repulsive Lennard-Jones potential and neighboring monomers on the chain are connected by finite extensible nonlinear elastic bonds. Each monomer is acted upon by a 1D asymmetric, piecewise linear potential of spatial period L comparable to the radius of gyration of the polymer. This potential is also characterized by a localization time, t(on), and by a free diffusion time, t(off). We characterize the average motor velocity as a function of L, t(off), and N to determine optimal parameter ranges, and we evaluate motor performance in terms of finite dispersion, Peclet number, rectification efficiency, stall force, and transportation of a load against a viscous drag. We find that the polymer motor performs qualitatively better than a single particle in a flashing ratchet: with increasing N, the polymer loses velocity much more slowly than expected in the absence of internal degrees of freedom, and the motor stall force increases linearly with N. To understand these cooperative aspects of motor operation, we analyze relevant Rouse modes. The experimental feasibility is analyzed and the parameters of the model are scaled to those of lambda-DNA. Finally, in the context of experimental realization, we present initial modeling results for a 2D flashing ratchet constructed using an electrode array, and find good agreement with the results of 1D simulations although the polymer in the 2D potential sometimes briefly "detaches" from the electrode surface.

Journal Article↗

PubMed2001

Control of chaotic Taylor-Couette flow with time-delayed feedback.

We demonstrate that unstable periodic orbits embedded in the experimental chaotic attractor determined by the Taylor-Couette flow can be stabilized with a time-delay autosynchronization algorithm. The optimal parameters of the feedback and their dependence on the control parameter are shown as experimental results.

Journal Article↗

PubMed2005

Allostery in a coarse-grained model of protein dynamics.

We propose a criterion for optimal parameter selection in coarse-grained models of proteins and develop a refined elastic network model (ENM) of bovine trypsinogen. The unimodal density-of-states distribution of the trypsinogen ENM disagrees with the bimodal distribution obtained from an all-atom model; however, the bimodal distribution is recovered by strengthening interactions between atoms that are backbone neighbors. We use the backbone-enhanced model to analyze allosteric mechanisms of trypsinogen and find relatively strong communication between the regulatory and active sites.

Algorithms↗

PubMed1995

Phase improvement by cross-validated density modification.

Solvent flattening is a useful constraint for the early stages of crystallographic structure determination. However, sometimes it fails to produce significant improvement of poor experimental or molecular-replacement phases. This often occurs as a result of incorrect parameterization. In addition, the potential of overfitting or misinterpretation of the data exists. We have implemented a cross-validated (or free) R value in order to reduce this risk. The free R value was calculated between the experimental F(obs)(h) and the calculated structure factors, F(sf)(h), obtained by inverse Fourier transformation of the solvent-flattened electron density. Because of the sensitivity of the free R value to the test set selection at low resolution complete cross-validation may be required. The reliability of this approach was assessed by examining the correlation between the free R value and the known phase errors for two test cases. A high correlation was found upon variation of the extent of negative density elimination, figure of merit estimation, and the relative weighting in the phase combination procedure. The free R value can be used to optimize parameters of density-modification procedures when independent phase error estimates are unavailable.

Journal Article↗