Frequent pathway mutations of splicing machinery in myelodysplasia.

Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (∼45 to ∼85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.

Patient and Caregiver Perceptions of an Interface Design to Communicate Artificial Intelligence-Based Prognosis for Patients With Advanced Solid Tumors.

PURPOSE: Use of artificial intelligence (AI) in cancer care is increasing. What remains unclear is how best to design patient-facing systems that communicate AI output. With oncologist input, we designed an interface that presents patient-specific, machine learning-based 6-month survival prognosis information designed to aid oncology providers in preparing for and discussing prognosis with patients with advanced solid tumors and their caregivers. The primary purpose of this study was to assess patient and caregiver perceptions and identify enhancements of the interface for communicating 6-month survival and other prognosis information when making treatment decisions concerning anticancer and supportive therapy. METHODS: This qualitative study included interviews and focus groups conducted between November and December 2022. Purposive sampling was used to recruit former patients with cancer and/or former caregivers of patients with cancer who had participated in cancer treatment decisions from Utah or elsewhere in the United States. Categories and themes related to perceptions of the interface were identified. RESULTS: We received feedback from 20 participants during eight individual interviews and two focus groups, including four cancer survivors, 13 caregivers, and three representing both. Overall, most participants expressed positive perceptions about the tool and identified its value for supporting decision making, feeling less alone, and supporting communication among oncologists, patients, and their caregivers. Participants identified areas for improvement and implementation considerations, particularly that oncologists should share the tool and guide discussions about prognosis with patients who want to receive the information. CONCLUSION: This study revealed important patient and caregiver perceptions of and enhancements for the proposed interface. Originally designed with input from oncology providers, patient and caregiver participants identified additional interface design recommendations and implementation considerations to support communication about prognosis.

Design of an interface to communicate artificial intelligence-based prognosis for patients with advanced solid tumors: a user-centered approach.

OBJECTIVES: To design an interface to support communication of machine learning (ML)-based prognosis for patients with advanced solid tumors, incorporating oncologists' needs and feedback throughout design. MATERIALS AND METHODS: Using an interdisciplinary user-centered design approach, we performed 5 rounds of iterative design to refine an interface, involving expert review based on usability heuristics, input from a color-blind adult, and 13 individual semi-structured interviews with oncologists. Individual interviews included patient vignettes and a series of interfaces populated with representative patient data and predicted survival for each treatment decision point when a new line of therapy (LoT) was being considered. Ongoing feedback informed design decisions, and directed qualitative content analysis of interview transcripts was used to evaluate usability and identify enhancement requirements. RESULTS: Design processes resulted in an interface with 7 sections, each addressing user-focused questions, supporting oncologists to "tell a story" as they discuss prognosis during a clinical encounter. The iteratively enhanced interface both triggered and reflected design decisions relevant when attempting to communicate ML-based prognosis, and exposed misassumptions. Clinicians requested enhancements that emphasized interpretability over explainability. Qualitative findings confirmed that previously identified issues were resolved and clarified necessary enhancements (eg, use months not days) and concerns about usability and trust (eg, address LoT received elsewhere). Appropriate use should be in the context of a conversation with an oncologist. CONCLUSION: User-centered design, ongoing clinical input, and a visualization to communicate ML-related outcomes are important elements for designing any decision support tool enabled by artificial intelligence, particularly when communicating prognosis risk.

Development of a Machine Learning Model Using Limited Features to Predict 6-Month Mortality at Treatment Decision Points for Patients With Advanced Solid Tumors.

PURPOSE: Patients with advanced solid tumors may receive intensive treatments near the end of life. This study aimed to create a machine learning (ML) model using limited features to predict 6-month mortality at treatment decision points (TDPs). METHODS: We identified a cohort of adults with advanced solid tumors receiving care at a major cancer center from 2014 to 2020. We identified TDPs for new lines of therapy (LoTs) and confirmed mortality at 6 months after a TDP. Using extreme gradient boosting, ML models were developed, which used or derived features from a limited set of electronic health record data considering the literature, clinical relevance, variability, availability, and predictive importance using Shapley additive explanations scores. We predicted and observed 6-month mortality after a TDP and assessed a risk stratification strategy with different risk thresholds to support communication of chance of survival. RESULTS: Four thousand one hundred ninety-two patients were included. Patients had 7,056 TDPs, for which the 6-month mortality increased from 17.9% to 46.7% after starting first to sixth LoT, respectively. On the basis of internal validation, models using both 111 (Full) or 45 (Limited-45) features accurately predicted 6-month mortality (area under the curve ≥ 0.80). Using a 0.3 risk threshold in the Limited-45 model, the observed 6-month survival was 34% (95% CI, 28 to 40) versus 81% (95% CI, 81 to 82) among those classified with low or higher chance of survival, respectively. The positive predictive value of the Limited-45 model was 0.66 (95% CI, 0.60 to 0.72). CONCLUSION: We developed and validated a ML model using a limited set of 45 features readily derived from electronic health record data to predict 6-month prognosis in patients with advanced solid tumors. The model output may support shared decision making as patients consider the next LoT.

ANCA-Associated Vasculitis May Result as a Complication to Both SARS-CoV-2 Infection and Vaccination.

In the last two years, our world experienced one of the most devastating and fast-exploding pandemic, due to the wide spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The scientific community managed to develop effective vaccines, the main weapons to shield the immune system and protect people. Nevertheless, both SARS-CoV-2 infection and the vaccination against it have been associated with the stimulation of inflammatory cells such as T and B lymphocytes that results in a cytokine storm, endothelial inflammation and vascular injury, which can lead to different types of vasculitis. We present the first case of de novo MPO-ANCA-associated vasculitis, which developed shortly after SARS-CoV-2 vaccination, adequately responded to treatment, and subsequently relapsed after COVID-19 infection. With this case, we indicate an etiological connection between viral infection and disease development, as well as the possibility of a common immune mechanism between SARS-CoV-2 infection and vaccination, that can stimulate vascular events and lead to vasculitis. There have been several case reports of de novo vasculitis, affecting large, medium, or small vessels, following either infection or vaccination against COVID-19, during the pandemic outbreak. We summarize previous reports and also analyze proposed pathogenic mechanisms between SARS-CoV-2 and vasculitis.

Leveraging Artificial Intelligence to Improve Chronic Disease Care: Methods and Application to Pharmacotherapy Decision Support for Type-2 Diabetes Mellitus.

OBJECTIVES: Artificial intelligence (AI), including predictive analytics, has great potential to improve the care of common chronic conditions with high morbidity and mortality. However, there are still many challenges to achieving this vision. The goal of this project was to develop and apply methods for enhancing chronic disease care using AI. METHODS: Using a dataset of 27,904 patients with diabetes, an analytical method was developed and validated for generating a treatment pathway graph which consists of models that predict the likelihood of alternate treatment strategies achieving care goals. An AI-driven clinical decision support system (CDSS) integrated with the electronic health record (EHR) was developed by encapsulating the prediction models in an OpenCDS Web service module and delivering the model outputs through a SMART on FHIR (Substitutable Medical Applications and Reusable Technologies on Fast Healthcare Interoperability Resources) web-based dashboard. This CDSS enables clinicians and patients to review relevant patient parameters, select treatment goals, and review alternate treatment strategies based on prediction results. RESULTS: The proposed analytical method outperformed previous machine-learning algorithms on prediction accuracy. The CDSS was successfully integrated with the Epic EHR at the University of Utah. CONCLUSION: A predictive analytics-based CDSS was developed and successfully integrated with the EHR through standards-based interoperability frameworks. The approach used could potentially be applied to many other chronic conditions to bring AI-driven CDSS to the point of care.

External Validation of a Machine Learning Model to Predict 6-Month Mortality for Patients With Advanced Solid Tumors.

This prognostic study performed external validation of a machine learning model to predict 6-month mortality among patients with advanced solid tumors.

A simple and highly sensitive spectroscopic fluorescence-detection system for multi-channel plastic-microchip electrophoresis based on side-entry laser-beam zigzag irradiation.

A five-color fluorescence-detection system for eight-channel plastic-microchip electrophoresis was developed. In the eight channels (with effective electrophoretic lengths of 10 cm), single-stranded DNA fragments were separated (with single-base resolution up to 300 bases within 10 min), and seventeen-loci STR genotyping for forensic human identification was successfully demonstrated. In the system, a side-entry laser beam is passed through the eight channels (eight A channels), with alternately arrayed seven sacrificial channels (seven B channels), by a technique called "side-entry laser-beam zigzag irradiation." Laser-induced fluorescence from the eight A channels and Raman-scattered light from the seven B channels are then simultaneously, uniformly, and spectroscopically detected, in the direction perpendicular to the channel array plane, through a transmission grating and a CCD camera. The system is therefore simple and highly sensitive. Because the microchip is fabricated by plastic-injection molding, it is inexpensive and disposable and thus suitable for actual use in various fields.