The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.

Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch's APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch's data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch's analytic tools by developing a customized plugin for OpenAI's ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app.

Automated treatment planning framework for brachytherapy of cervical cancer using 3D dose predictions.

Objective. To lay the foundation for automated knowledge-based brachytherapy treatment planning using 3D dose estimations, we describe an optimization framework to convert brachytherapy dose distributions directly into dwell times (DTs).Approach. A dose rate kerneld(r,θ,φ)was produced by exporting 3D dose for one dwell position from the treatment planning system and normalizing by DT. By translating and rotating this kernel to each dwell position, scaling by DT and summing over all dwell positions, dose was computed (Dcalc). We used a Python-coded COBYLA optimizer to iteratively determine the DTs that minimize the mean squared error betweenDcalcand reference doseDref, computed using voxels withDref80%-120% of prescription. As validation of the optimization, we showed that the optimizer replicates clinical plans whenDref= clinical dose in 40 patients treated with tandem-and-ovoid (T&O) or tandem-and-ring (T&R) and 0-3 needles. Then we demonstrated automated planning in 10 T&O usingDref= dose predicted from a convolutional neural network developed in past work. Validation and automated plans were compared to clinical plans using mean absolute differences (MAD=1N∑n=1Nabsxn-xn') over all voxels (xn= Dose,N= #voxels) and DTs (xn= DT,N= #dwell positions), mean differences (MD) in organD2ccand high-risk CTV D90 over all patients (where positive indicates higher clinical dose), and mean Dice similarity coefficients (DSC) for 100% isodose contours.Main results. Validation plans agreed well with clinical plans (MADdose= 1.1%, MADDT= 4 s or 0.8% of total plan time,D2ccMD = -0.2% to 0.2% and D90 MD = -0.6%, DSC = 0.99). For automated plans, MADdose= 6.5% and MADDT= 10.3 s (2.1%). The slightly higher clinical metrics in automated plans (D2ccMD = -3.8% to 1.3% and D90 MD = -5.1%) were due to higher neural network dose predictions. The overall shape of the automated dose distributions were similar to clinical doses (DSC = 0.91).Significance. Automated planning with 3D dose predictions could provide significant time savings and standardize treatment planning across practitioners, regardless of experience.

Knowledge-based three-dimensional dose prediction for tandem-and-ovoid brachytherapy.

PURPOSE: The purpose of this work was to develop a knowledge-based dose prediction system using a convolution neural network (CNN) for cervical brachytherapy treatments with a tandem-and-ovoid applicator. METHODS: A 3D U-NET CNN was utilized to make voxel-wise dose predictions based on organ-at-risk (OAR), high-risk clinical target volume (HRCTV), and possible source location geometry. The model comprised 395 previously treated cases: training (273), validation (61), test (61). To assess voxel prediction accuracy, we evaluated dose differences in all cohorts across the dose range of 20-130% of prescription, mean (SD) and standard deviation (σ), as well as isodose dice similarity coefficients for clinical and/or predicted dose distributions. We examined discrete Dose-Volume Histogram (DVH) metrics utilized for brachytherapy plan quality assessment (HRCTV D90%; bladder, rectum, and sigmoid D2cc) with ΔDx=Dx,actual-Dx,predicted mean, standard deviation, and Pearson correlation coefficient further quantifying model performance. RESULTS: Ranges of voxel-wise dose difference accuracy (δD¯±σ) for 20-130% dose interval in training (test) sets ranged from [-0.5% ± 2.0% to +2.0% ± 14.0%] ([-0.1% ± 4.0% to +4.0% ± 26.0%]) in all voxels, [-1.7% ± 5.1% to -3.5% ± 12.8%] ([-2.9% ± 4.8% to -2.6% ± 18.9%]) in HRCTV, [-0.02% ± 2.40% to +3.2% ± 12.0%] ([-2.5% ± 3.6% to +0.8% ± 12.7%]) in bladder, [-0.7% ± 2.4% to +15.5% ± 11.0%] ([-0.9% ± 3.2% to +27.8% ± 11.6%]) in rectum, and [-0.7% ± 2.3% to +10.7% ± 15.0%] ([-0.4% ± 3.0% to +18.4% ± 11.4%]) in sigmoid. Isodose dice similarity coefficients ranged from [0.96,0.91] for training and [0.94,0.87] for test cohorts. Relative DVH metric prediction in the training (test) set were HRCTV ΔD¯90±σΔD = -0.19 ± 0.55Gy (-0.09 ± 0.67 Gy), bladder ΔD¯2cc±σΔD = -0.06 ± 0.54Gy (-0.17 ± 0.67 Gy), rectum ΔD¯2cc±σΔD= -0.03 ± 0.36Gy (-0.04 ± 0.46 Gy), and sigmoid ΔD¯2cc±σΔD = -0.01 ± 0.34Gy (0.00 ± 0.44 Gy). CONCLUSIONS: A 3D knowledge-based dose predictions provide voxel-level and DVH metric estimates that could be used for treatment plan quality control and data-driven plan guidance.