Personalizing the first dose of FSH for IVF/ICSI patients through machine learning: a non-inferiority study protocol for a multi-center randomized controlled trial.

BACKGROUND: Adequately selecting the initial follicle-stimulating hormone (FSH) dose during controlled ovarian stimulation (COS) is key for success in assisted reproduction. The objective of COS is to obtain an optimal number of oocytes to increase the chances of achieving a pregnancy, while avoiding complications for the patient. Current clinical protocols do achieve good results for the majority of patients, but further refinements in individualized FSH dosing may reduce the risk of poor ovarian response while also limiting the risk of ovarian hyperstimulation syndrome (OHSS) risk. Models to select the first FSH dose in COS have been presented in literature with promising results. However, most have only been developed and tested in normo-ovulatory women under the age of 40 years. METHODS: This is a randomized, controlled, multicenter, single blinded, clinical trial. This study will be performed in 236 first cycle in vitro fertilization (IVF) and/or ICSI (intracytoplasmic sperm injection) patients, randomized 1:1 in two arms. In the intervention arm, the dose of FSH will be assigned by a machine learning (ML) model called IDoser, while in the control arm, the dose will be determined by the clinician following standard practice. Stratified block randomization will be carried out depending on the patient being classified as expected low responder, high responder, or normo-responder. Patients will complete their participation in the trial once the first embryo transfer result is known. The primary outcome of the study is the number of metaphase II (MII) oocytes retrieved at ovarian pick up (OPU) and the hypothesis of non-inferiority of the intervention arm compared to the control. Secondary outcomes include the number of cycle cancelations (due to low response or no retrieval of mature oocytes), risk of ovarian hyperstimulation syndrome (OHSS), and clinical pregnancy and live birth rates per first transfer. DISCUSSION: To our knowledge, this is the first randomized trial to test clinical performance of an all-patient inclusive model to select the first dose of FSH for COS. Prospective trials for machine learning (ML) models in healthcare are scarce but necessary for clinical application. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05948293 . Registered on 14 July 2023.

Manual versus deep learning measurements to evaluate cumulus expansion of bovine oocytes and its relationship with embryo development in vitro.

Cumulus expansion is an important indicator of oocyte maturation and has been suggested to be indicative of greater oocyte developmental capacity. Although multiple methods have been described to assess cumulus expansion, none of them is considered a gold standard. Additionally, these methods are subjective and time-consuming. In this manuscript, the reliability of three cumulus expansion measurement methods was assessed, and a deep learning model was created to automatically perform the measurement. Cumulus expansion of 232 cumulus-oocyte complexes was evaluated by three independent observers using three methods: (1) measurement of the cumulus area, (2) measurement of three distances between the zona pellucida and outer cumulus, and (3) scoring cumulus expansion on a 5-point Likert scale. The reliability of the methods was calculated in terms of intraclass-correlation coefficients (ICC) for both inter- and intra-observer agreements. The area method resulted in the best overall inter-observer agreement with an ICC of 0.89 versus 0.54 and 0.30 for the 3-distance and scoring methods, respectively. Therefore, the area method served as the base to create a deep learning model, AI-xpansion, which reaches a human-level performance in terms of average rank, bias and variance. To evaluate the accuracy of the methods, the results of cumulus expansion calculations were linked to embryonic development. Cumulus expansion had increased significantly in oocytes that achieved successful embryo development when measured by AI-xpansion, the area- or 3-distance method, while this was not the case for the scoring method. Measuring the area is the most reliable method to manually evaluate cumulus expansion, whilst deep learning automatically performs the calculation with human-level precision and high accuracy and could therefore be a valuable prospective tool for embryologists.

Using Machine Learning Technology (Early Artificial Intelligence-Supported Response With Social Listening Platform) to Enhance Digital Social Understanding for the COVID-19 Infodemic: Development and Implementation Study.

BACKGROUND: Amid the COVID-19 pandemic, there has been a need for rapid social understanding to inform infodemic management and response. Although social media analysis platforms have traditionally been designed for commercial brands for marketing and sales purposes, they have been underused and adapted for a comprehensive understanding of social dynamics in areas such as public health. Traditional systems have challenges for public health use, and new tools and innovative methods are required. The World Health Organization Early Artificial Intelligence-Supported Response with Social Listening (EARS) platform was developed to overcome some of these challenges. OBJECTIVE: This paper describes the development of the EARS platform, including data sourcing, development, and validation of a machine learning categorization approach, as well as the results from the pilot study. METHODS: Data for EARS are collected daily from web-based conversations in publicly available sources in 9 languages. Public health and social media experts developed a taxonomy to categorize COVID-19 narratives into 5 relevant main categories and 41 subcategories. We developed a semisupervised machine learning algorithm to categorize social media posts into categories and various filters. To validate the results obtained by the machine learning-based approach, we compared it to a search-filter approach, applying Boolean queries with the same amount of information and measured the recall and precision. Hotelling T2 was used to determine the effect of the classification method on the combined variables. RESULTS: The EARS platform was developed, validated, and applied to characterize conversations regarding COVID-19 since December 2020. A total of 215,469,045 social posts were collected for processing from December 2020 to February 2022. The machine learning algorithm outperformed the Boolean search filters method for precision and recall in both English and Spanish languages (P<.001). Demographic and other filters provided useful insights on data, and the gender split of users in the platform was largely consistent with population-level data on social media use. CONCLUSIONS: The EARS platform was developed to address the changing needs of public health analysts during the COVID-19 pandemic. The application of public health taxonomy and artificial intelligence technology to a user-friendly social listening platform, accessible directly by analysts, is a significant step in better enabling understanding of global narratives. The platform was designed for scalability; iterations and new countries and languages have been added. This research has shown that a machine learning approach is more accurate than using only keywords and has the benefit of categorizing and understanding large amounts of digital social data during an infodemic. Further technical developments are needed and planned for continuous improvements, to meet the challenges in the generation of infodemic insights from social media for infodemic managers and public health professionals.

Modeling three sources of uncertainty in assisted reproductive technologies with probabilistic graphical models.

Embryo selection is a critical step in assisted reproduction: good selection criteria are expected to increase the probability of inducing a pregnancy. Machine learning techniques have been applied for implantation prediction or embryo quality assessment, which embryologists can use to make a decision about embryo selection. However, this is a highly uncertain real-world problem, and current proposals do not model always all the sources of uncertainty. We present a novel probabilistic graphical model that accounts for three different sources of uncertainty, the standard embryo and cycle viability, and a third one that represents any unknown factor that can drive a treatment to a failure in otherwise perfect conditions. We derive a parametric learning method based on the Expectation-Maximization strategy, which accounts for uncertainty issues. We empirically analyze the model within a real database consisting of 604 cycles (3125 embryos) carried out at Hospital Donostia (Spain). Embryologists followed the protocol of the Spanish Association for Reproduction Biology Studies (ASEBIR), based on morphological features, for embryo selection. Our model predictions are correlated with the ASEBIR protocol, which validates our model. The benefits of accounting for the different sources of uncertainty and the importance of the cycle characteristics are shown. Considering only transferred embryos, our model does not further discriminate them as implanted or failed, suggesting that the ASEBIR protocol could be understood as a thorough summary of the available morphological features.

Supporting first FSH dosage for ovarian stimulation with machine learning.

RESEARCH QUESTION: Is it possible to identify accurately the optimal first dose of FSH in ovarian stimulation by means of a machine learning model? DESIGN: Observational study (2011-2021) including first IVF cycles with own oocytes. A total of 2713 patients from five private reproductive centres were included in the development phase (2011-2019) and 774 in the validation phase (2020-2021). Predictor variables included age, BMI, AMH, AFC and previous live births. Performance was measured with a proposed score based on the number of MII oocytes retrieved and dose received, recommended, or both. RESULTS: The included cycles were from women aged 37.7 ± 4.4 years (18-45 years), with a BMI of 23.5 ± 4.2 kg/m2, AMH of 2.4 ± 2.3 ng/ml, AFC of 11.3 ± 7.6, and an average number of MII obtained 6.9 ± 5.4. The model reached a mean performance score of 0.87 (95% CI 0.86 to 0.88) in the development phase, significantly better than for doses prescribed by clinicians for the same patients (0.83, 95% CI 0.82 to 0.84; P = 2.44 e-10). Mean performance score of the model recommendations was 0.89 (95% CI 0.88 to 0.90) in the validation phase, also significantly better than clinicians (0.84, 95% CI 0.82 to 0.86; P = 3.81 e-05). The model was shown to surpass the performance of standard practice. CONCLUSION: This machine learning model could be used as a training and learning tool for new clinicians, and as quality control for experienced clinicians.

Enriched Music-supported Therapy for chronic stroke patients: a study protocol of a randomised controlled trial.

BACKGROUND: Residual motor deficits of the upper limb in patients with chronic stroke are common and have a negative impact on autonomy, participation and quality of life. Music-Supported Therapy (MST) is an effective intervention to enhance motor and cognitive function, emotional well-being and quality of life in chronic stroke patients. We have adapted the original MST training protocol to a home-based intervention, which incorporates increased training intensity and variability, group sessions, and optimisation of learning to promote autonomy and motivation. METHODS: A randomised controlled trial will be conducted to test the effectiveness of this enriched MST (eMST) protocol in improving motor functions, cognition, emotional well-being and quality of life of chronic stroke patients when compared to a program of home-based exercises utilizing the Graded Repetitive Arm Supplementary Program (GRASP). Sixty stroke patients will be recruited and randomly allocated to an eMST group (n = 30) or a control GRASP intervention group (n = 30). Patients will be evaluated before and after a 10-week intervention, as well as at 3-month follow-up. The primary outcome of the study is the functionality of the paretic upper limb measured with the Action Research Arm Test. Secondary outcomes include other motor and cognitive functions, emotional well-being and quality of life measures as well as self-regulation and self-efficacy outcomes. DISCUSSION: We hypothesize that patients treated with eMST will show larger improvements in their motor and cognitive functions, emotional well-being and quality of life than patients treated with a home-based GRASP intervention. TRIAL REGISTRATION: The trial has been registered at ClinicalTrials.gov and identified as NCT04507542 on 8 August 2020.

A Robust Solution to Variational Importance Sampling of Minimum Variance.

Importance sampling is a Monte Carlo method where samples are obtained from an alternative proposal distribution. This can be used to focus the sampling process in the relevant parts of space, thus reducing the variance. Selecting the proposal that leads to the minimum variance can be formulated as an optimization problem and solved, for instance, by the use of a variational approach. Variational inference selects, from a given family, the distribution which minimizes the divergence to the distribution of interest. The Rényi projection of order 2 leads to the importance sampling estimator of minimum variance, but its computation is very costly. In this study with discrete distributions that factorize over probabilistic graphical models, we propose and evaluate an approximate projection method onto fully factored distributions. As a result of our evaluation it becomes apparent that a proposal distribution mixing the information projection with the approximate Rényi projection of order 2 could be interesting from a practical perspective.

Combining phylogenetic footprinting with motif models incorporating intra-motif dependencies.

BACKGROUND: Transcriptional gene regulation is a fundamental process in nature, and the experimental and computational investigation of DNA binding motifs and their binding sites is a prerequisite for elucidating this process. Approaches for de-novo motif discovery can be subdivided in phylogenetic footprinting that takes into account phylogenetic dependencies in aligned sequences of more than one species and non-phylogenetic approaches based on sequences from only one species that typically take into account intra-motif dependencies. It has been shown that modeling (i) phylogenetic dependencies as well as (ii) intra-motif dependencies separately improves de-novo motif discovery, but there is no approach capable of modeling both (i) and (ii) simultaneously. RESULTS: Here, we present an approach for de-novo motif discovery that combines phylogenetic footprinting with motif models capable of taking into account intra-motif dependencies. We study the degree of intra-motif dependencies inferred by this approach from ChIP-seq data of 35 transcription factors. We find that significant intra-motif dependencies of orders 1 and 2 are present in all 35 datasets and that intra-motif dependencies of order 2 are typically stronger than those of order 1. We also find that the presented approach improves the classification performance of phylogenetic footprinting in all 35 datasets and that incorporating intra-motif dependencies of order 2 yields a higher classification performance than incorporating such dependencies of only order 1. CONCLUSION: Combining phylogenetic footprinting with motif models incorporating intra-motif dependencies leads to an improved performance in the classification of transcription factor binding sites. This may advance our understanding of transcriptional gene regulation and its evolution.

Unrealistic phylogenetic trees may improve phylogenetic footprinting.

MOTIVATION: The computational investigation of DNA binding motifs from binding sites is one of the classic tasks in bioinformatics and a prerequisite for understanding gene regulation as a whole. Due to the development of sequencing technologies and the increasing number of available genomes, approaches based on phylogenetic footprinting become increasingly attractive. Phylogenetic footprinting requires phylogenetic trees with attached substitution probabilities for quantifying the evolution of binding sites, but these trees and substitution probabilities are typically not known and cannot be estimated easily. RESULTS: Here, we investigate the influence of phylogenetic trees with different substitution probabilities on the classification performance of phylogenetic footprinting using synthetic and real data. For synthetic data we find that the classification performance is highest when the substitution probability used for phylogenetic footprinting is similar to that used for data generation. For real data, however, we typically find that the classification performance of phylogenetic footprinting surprisingly increases with increasing substitution probabilities and is often highest for unrealistically high substitution probabilities close to one. This finding suggests that choosing realistic model assumptions might not always yield optimal predictions in general and that choosing unrealistically high substitution probabilities close to one might actually improve the classification performance of phylogenetic footprinting. AVAILABILITY AND IMPLEMENTATION: The proposed PF is implemented in JAVA and can be downloaded from https://github.com/mgledi/PhyFoo. CONTACT: : martin.nettling@informatik.uni-halle.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Detecting and correcting the binding-affinity bias in ChIP-seq data using inter-species information.

BACKGROUND: Transcriptional gene regulation is a fundamental process in nature, and the experimental and computational investigation of DNA binding motifs and their binding sites is a prerequisite for elucidating this process. ChIP-seq has become the major technology to uncover genomic regions containing those binding sites, but motifs predicted by traditional computational approaches using these data are distorted by a ubiquitous binding-affinity bias. Here, we present an approach for detecting and correcting this bias using inter-species information. RESULTS: We find that the binding-affinity bias caused by the ChIP-seq experiment in the reference species is stronger than the indirect binding-affinity bias in orthologous regions from phylogenetically related species. We use this difference to develop a phylogenetic footprinting model that is capable of detecting and correcting the binding-affinity bias. We find that this model improves motif prediction and that the corrected motifs are typically softer than those predicted by traditional approaches. CONCLUSIONS: These findings indicate that motifs published in databases and in the literature are artificially sharpened compared to the native motifs. These findings also indicate that our current understanding of transcriptional gene regulation might be blurred, but that it is possible to advance this understanding by taking into account inter-species information available today and even more in the future.