Embryologist agreement when assessing blastocyst implantation probability: is data-driven prediction the solution to embryo assessment subjectivity?

STUDY QUESTION: What is the accuracy and agreement of embryologists when assessing the implantation probability of blastocysts using time-lapse imaging (TLI), and can it be improved with a data-driven algorithm? SUMMARY ANSWER: The overall interobserver agreement of a large panel of embryologists was moderate and prediction accuracy was modest, while the purpose-built artificial intelligence model generally resulted in higher performance metrics. WHAT IS KNOWN ALREADY: Previous studies have demonstrated significant interobserver variability amongst embryologists when assessing embryo quality. However, data concerning embryologists' ability to predict implantation probability using TLI is still lacking. Emerging technologies based on data-driven tools have shown great promise for improving embryo selection and predicting clinical outcomes. STUDY DESIGN, SIZE, DURATION: TLI video files of 136 embryos with known implantation data were retrospectively collected from two clinical sites between 2018 and 2019 for the performance assessment of 36 embryologists and comparison with a deep neural network (DNN). PARTICIPANTS/MATERIALS, SETTING, METHODS: We recruited 39 embryologists from 13 different countries. All participants were blinded to clinical outcomes. A total of 136 TLI videos of embryos that reached the blastocyst stage were used for this experiment. Each embryo's likelihood of successfully implanting was assessed by 36 embryologists, providing implantation probability grades (IPGs) from 1 to 5, where 1 indicates a very low likelihood of implantation and 5 indicates a very high likelihood. Subsequently, three embryologists with over 5 years of experience provided Gardner scores. All 136 blastocysts were categorized into three quality groups based on their Gardner scores. Embryologist predictions were then converted into predictions of implantation (IPG ≥ 3) and no implantation (IPG ≤ 2). Embryologists' performance and agreement were assessed using Fleiss kappa coefficient. A 10-fold cross-validation DNN was developed to provide IPGs for TLI video files. The model's performance was compared to that of the embryologists. MAIN RESULTS AND THE ROLE OF CHANCE: Logistic regression was employed for the following confounding variables: country of residence, academic level, embryo scoring system, log years of experience and experience using TLI. None were found to have a statistically significant impact on embryologist performance at α = 0.05. The average implantation prediction accuracy for the embryologists was 51.9% for all embryos (N = 136). The average accuracy of the embryologists when assessing top quality and poor quality embryos (according to the Gardner score categorizations) was 57.5% and 57.4%, respectively, and 44.6% for fair quality embryos. Overall interobserver agreement was moderate (κ = 0.56, N = 136). The best agreement was achieved in the poor + top quality group (κ = 0.65, N = 77), while the agreement in the fair quality group was lower (κ = 0.25, N = 59). The DNN showed an overall accuracy rate of 62.5%, with accuracies of 62.2%, 61% and 65.6% for the poor, fair and top quality groups, respectively. The AUC for the DNN was higher than that of the embryologists overall (0.70 DNN vs 0.61 embryologists) as well as in all of the Gardner groups (DNN vs embryologists-Poor: 0.69 vs 0.62; Fair: 0.67 vs 0.53; Top: 0.77 vs 0.54). LIMITATIONS, REASONS FOR CAUTION: Blastocyst assessment was performed using video files acquired from time-lapse incubators, where each video contained data from a single focal plane. Clinical data regarding the underlying cause of infertility and endometrial thickness before the transfer was not available, yet may explain implantation failure and lower accuracy of IPGs. Implantation was defined as the presence of a gestational sac, whereas the detection of fetal heartbeat is a more robust marker of embryo viability. The raw data were anonymized to the extent that it was not possible to quantify the number of unique patients and cycles included in the study, potentially masking the effect of bias from a limited patient pool. Furthermore, the lack of demographic data makes it difficult to draw conclusions on how representative the dataset was of the wider population. Finally, embryologists were required to assess the implantation potential, not embryo quality. Although this is not the traditional approach to embryo evaluation, morphology/morphokinetics as a means of assessing embryo quality is believed to be strongly correlated with viability and, for some methods, implantation potential. WIDER IMPLICATIONS OF THE FINDINGS: Embryo selection is a key element in IVF success and continues to be a challenge. Improving the predictive ability could assist in optimizing implantation success rates and other clinical outcomes and could minimize the financial and emotional burden on the patient. This study demonstrates moderate agreement rates between embryologists, likely due to the subjective nature of embryo assessment. In particular, we found that average embryologist accuracy and agreement were significantly lower for fair quality embryos when compared with that for top and poor quality embryos. Using data-driven algorithms as an assistive tool may help IVF professionals increase success rates and promote much needed standardization in the IVF clinic. Our results indicate a need for further research regarding technological advancement in this field. STUDY FUNDING/COMPETING INTEREST(S): Embryonics Ltd is an Israel-based company. Funding for the study was partially provided by the Israeli Innovation Authority, grant #74556. TRIAL REGISTRATION NUMBER: N/A.

Real-time prediction of patient disposition and the impact of reporter confidence on mid-level triage accuracies: an observational study in Israel.

AIM: The emergency department (ED) is the first port-of-call for most patients receiving hospital care and as such acts as a gatekeeper to the wards, directing patient flow through the hospital. ED overcrowding is a well-researched field and negatively affects patient outcome, staff well-being and hospital reputation. An accurate, real-time model capable of predicting ED overcrowding has obvious merit in a world becoming increasingly computational, although the complicated dynamics of the department have hindered international efforts to design such a model. Triage nurses' assessments have been shown to be accurate predictors of patient disposition and could, therefore, be useful input for overcrowding and patient flow models. METHODS: In this study, we assess the prediction capabilities of triage nurses in a level 1 urban hospital in central Israeli. ED settings included both acute and ambulatory wings. Nurses were asked to predict admission or discharge for each patient over a 3-month period as well as exact admission destination. Prediction confidence was used as an optimisation variable. RESULT: Triage nurses accurately predicted whether the patient would be admitted or discharged in 77% of patients in the acute wing, rising to 88% when their prediction certainty was high. Accuracies were higher still for patients in the ambulatory wing. In particular, negative predictive values for admission were highly accurate at 90%, irrespective of area or certainty levels. CONCLUSION: Nurses prediction of disposition should be considered for input for real-time ED models.

Syncope and undifferentiated shock.

Ventricular free wall rupture is a rare post myocardial complication with a high associated mortality. In this article we discuss the case of an elderly patient who presented to our emergency department in shock after an episode of syncope. Using Point Of Care Ultrasound (POCUS), identification of cardiac tamponade and pericardial thrombus was possible, signs indicating a diagnosis of free wall rupture. Early initiation of transfer proceedings to a tertiary cardio-thoracic unit was therefore possible, resulting in a positive patient outcome.

Medical expertise as a critical influencing factor on the length of stay in the ED: A retrospective cohort study.

ABSTRACT: Overcrowding in the emergency departments (ED) is a significant issue associated with increased morbidity and mortality rates as well as decreased patient satisfaction. Length of stay (LOS) is both a cause and a result of overcrowding. In Israel, as there are few emergency medicine (EM) physicians, the ED team is supplemented with doctors from specialties including internal medicine, general surgery, orthopedics etc. Here we compare ED length of stay (ED-LOS), treatment time and decision time between EM physicians, internists and general surgeons.A retrospective cohort study was conducted examining the Emergency Department length of stay (ED-LOS) for all adult patients attending Sheba Medical Center ED, Israel, between January 1st, and December 31st, 2014. Using electronic medical records, data was gathered on patient age, sex, primary ED physician, diagnosis, eventual disposition, treatment time and disposition decision time. The primary outcome variable was ED-LOS relative to case physician specialty and level (ED, internal medicine or surgery; specialist or resident). Secondary analysis was conducted on time to treatment/ decision as well as ED-LOS relative to patient classification variables (internal medicine vs surgical diagnosis). Specialists were compared to specialists and residents to residents for all outcomes.Residents and specialists in either EM, internal medicine or general surgery attended 57,486 (51.50%) of 111,630 visits to Sheba Hospital's general ED. Mean ED-LOS was 4.12 ±â€Š3.18 hours. Mean treatment time and decision time were 1.79 ±â€Š1.82 hours, 2.84 ±â€Š2.17 hours respectively. Amongst specialists, ED-LOS was shorter for EM physicians than for internal medicine physicians (mean difference 0.28 hours, 95% CI 0.14-0.43) and general surgeons (mean difference 0.63 hours, 95% CI 0.43-0.83). There was no statistical significance between residents when comparing outcomes.Increasing the number of EM specialists in the ED may support efforts to decrease ED-LOS, overcrowding and medical errors whilst increasing patient satisfaction and outcomes.

Complete vertebrate mitogenomes reveal widespread repeats and gene duplications.

BACKGROUND: Modern sequencing technologies should make the assembly of the relatively small mitochondrial genomes an easy undertaking. However, few tools exist that address mitochondrial assembly directly. RESULTS: As part of the Vertebrate Genomes Project (VGP) we develop mitoVGP, a fully automated pipeline for similarity-based identification of mitochondrial reads and de novo assembly of mitochondrial genomes that incorporates both long (> 10 kbp, PacBio or Nanopore) and short (100-300 bp, Illumina) reads. Our pipeline leads to successful complete mitogenome assemblies of 100 vertebrate species of the VGP. We observe that tissue type and library size selection have considerable impact on mitogenome sequencing and assembly. Comparing our assemblies to purportedly complete reference mitogenomes based on short-read sequencing, we identify errors, missing sequences, and incomplete genes in those references, particularly in repetitive regions. Our assemblies also identify novel gene region duplications. The presence of repeats and duplications in over half of the species herein assembled indicates that their occurrence is a principle of mitochondrial structure rather than an exception, shedding new light on mitochondrial genome evolution and organization. CONCLUSIONS: Our results indicate that even in the "simple" case of vertebrate mitogenomes the completeness of many currently available reference sequences can be further improved, and caution should be exercised before claiming the complete assembly of a mitogenome, particularly from short reads alone.

Production and single-step purification of EGFP and a biotinylated version of the Human Rhinovirus 14 3C protease.

The fluorescent reporter enhanced Green Fluorescent Protein (EGFP) has been used for assaying a wide range of biological activities ranging from gene expression, or localization of target proteins through to intermolecular interactions. However, over-production of this protein in Escherichia coli has resulted in the presence of inclusion bodies, which complicates recovery of the protein in significant quantities. In this paper, we describe a single-step method for isolating the protein from a Glutathione-S-Transferase (GST) fusion protein, release of the EGFP protein from the fusion was demonstrated using a biotinylated variant of Human Rhinovirus 14 3C protease that we have also constructed. We also suggest the potential uses of the biotinylated protease for bionanotechnology and synthetic biology.