Dataset Information

Treatment of evolving cancers will require dynamic decision support.

ABSTRACT: Cancer research has traditionally focused on developing new agents, but an underexplored question is that of the dose and frequency of existing drugs. Based on the modus operandi established in the early days of chemotherapies, most drugs are administered according to predetermined schedules that seek to deliver the maximum tolerated dose and are only adjusted for toxicity. However, we believe that the complex, evolving nature of cancer requires a more dynamic and personalized approach. Chronicling the milestones of the field, we show that the impact of schedule choice crucially depends on processes driving treatment response and failure. As such, cancer heterogeneity and evolution dictate that a one-size-fits-all solution is unlikely-instead, each patient should be mapped to the strategy that best matches their current disease characteristics and treatment objectives (i.e. their 'tumorscape'). To achieve this level of personalization, we need mathematical modeling. In this perspective, we propose a five-step 'Adaptive Dosing Adjusted for Personalized Tumorscapes (ADAPT)' paradigm to integrate data and understanding across scales and derive dynamic and personalized schedules. We conclude with promising examples of model-guided schedule personalization and a call to action to address key outstanding challenges surrounding data collection, model development, and integration.

SUBMITTER: Strobl MAR

PROVIDER: S-EPMC10688269 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Treatment of evolving cancers will require dynamic decision support.

Strobl M A R MAR Gallaher J J Robertson-Tessi M M West J J Anderson A R A ARA

Annals of oncology : official journal of the European Society for Medical Oncology 20231001 10

Cancer research has traditionally focused on developing new agents, but an underexplored question is that of the dose and frequency of existing drugs. Based on the modus operandi established in the early days of chemotherapies, most drugs are administered according to predetermined schedules that seek to deliver the maximum tolerated dose and are only adjusted for toxicity. However, we believe that the complex, evolving nature of cancer requires a more dynamic and personalized approach. Chronicl ...[more]

PMID: 37777307

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Project description:Clinical Decision Support Systems (CDSS) have the potential to improve and standardise care with probabilistic guidance. However, many CDSS deploy static, generic rule-based logic, resulting in inequitably distributed accuracy and inconsistent performance in evolving clinical environments. Data-driven models could resolve this issue by updating predictions according to the data collected. However, the size of data required necessitates collaborative learning from analogous CDSS's, which are often imperfectly interoperable (IIO) or unshareable. We propose Modular Clinical Decision Support Networks (MoDN) which allow flexible, privacy-preserving learning across IIO datasets, as well as being robust to the systematic missingness common to CDSS-derived data, while providing interpretable, continuous predictive feedback to the clinician. MoDN is a novel decision tree composed of feature-specific neural network modules that can be combined in any number or combination to make any number or combination of diagnostic predictions, updatable at each step of a consultation. The model is validated on a real-world CDSS-derived dataset, comprising 3,192 paediatric outpatients in Tanzania. MoDN significantly outperforms 'monolithic' baseline models (which take all features at once at the end of a consultation) with a mean macro F1 score across all diagnoses of 0.749 vs 0.651 for logistic regression and 0.620 for multilayer perceptron (p < 0.001). To test collaborative learning between IIO datasets, we create subsets with various percentages of feature overlap and port a MoDN model trained on one subset to another. Even with only 60% common features, fine-tuning a MoDN model on the new dataset or just making a composite model with MoDN modules matched the ideal scenario of sharing data in a perfectly interoperable setting. MoDN integrates into consultation logic by providing interpretable continuous feedback on the predictive potential of each question in a CDSS questionnaire. The modular design allows it to compartmentalise training updates to specific features and collaboratively learn between IIO datasets without sharing any data.

Project description:PurposePreservation surgery can halt the progress of joint degradation, preserving the life of the hip; however, outcome depends on the existing cartilage quality. Biochemical analysis of the hip cartilage utilizing MRI sequences such as delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), in addition to morphological analysis, can be used to detect early signs of cartilage degradation. However, a complete, accurate 3D analysis of the cartilage regions and layers is currently not possible due to a lack of diagnostic tools.MethodsA system for the efficient automatic parametrization of the 3D hip cartilage was developed. 2D U-nets were trained on manually annotated dual-flip angle (DFA) dGEMRIC for femoral head localization and cartilage segmentation. A fully automated cartilage sectioning pipeline for analysis of central and peripheral regions, femoral-acetabular layers, and a variable number of section slices, was developed along with functionality for the automatic calculation of dGEMRIC index, thickness, surface area, and volume.ResultsThe trained networks locate the femoral head and segment the cartilage with a Dice similarity coefficient of 88 ± 3 and 83 ± 4% on DFA and magnetization-prepared 2 rapid gradient-echo (MP2RAGE) dGEMRIC, respectively. A completely automatic cartilage analysis was performed in 18s, and no significant difference for average dGEMRIC index, volume, surface area, and thickness calculated on manual and automatic segmentation was observed.ConclusionAn application for the 3D analysis of hip cartilage was developed for the automated detection of subtle morphological and biochemical signs of cartilage degradation in prognostic studies and clinical diagnosis. The segmentation network achieved a 4-time increase in processing speed without loss of segmentation accuracy on both normal and deformed anatomy, enabling accurate parametrization. Retraining of the networks with the promising MP2RAGE protocol would enable analysis without the need for B1 inhomogeneity correction in the future.

Project description:BackgroundThe increasing affordability of DNA sequencing has allowed it to be widely deployed in pathology laboratories. However, this has exposed many issues with the analysis and reporting of variants for clinical diagnostic use. Implementing a high-throughput sequencing (NGS) clinical reporting system requires a diverse combination of capabilities, statistical methods to identify variants, global variant databases, a validated bioinformatics pipeline, an auditable laboratory workflow, reproducible clinical assays and quality control monitoring throughout. These capabilities must be packaged in software that integrates the disparate components into a useable system.ResultsTo meet these needs, we developed a web-based application, PathOS, which takes variant data from a patient sample through to a clinical report. PathOS has been used operationally in the Peter MacCallum Cancer Centre for two years for the analysis, curation and reporting of genetic tests for cancer patients, as well as the curation of large-scale research studies. PathOS has also been deployed in cloud environments allowing multiple institutions to use separate, secure and customisable instances of the system. Increasingly, the bottleneck of variant curation is limiting the adoption of clinical sequencing for molecular diagnostics. PathOS is focused on providing clinical variant curators and pathology laboratories with a decision support system needed for personalised medicine. While the genesis of PathOS has been within cancer molecular diagnostics, the system is applicable to NGS clinical reporting generally.ConclusionsThe widespread availability of genomic sequencers has highlighted the limited availability of software to support clinical decision-making in molecular pathology. PathOS is a system that has been developed and refined in a hospital laboratory context to meet the needs of clinical diagnostics. The software is available as a set of Docker images and source code at https://github.com/PapenfussLab/PathOS .

Dataset Information

Treatment of evolving cancers will require dynamic decision support.

Publications

Treatment of evolving cancers will require dynamic decision support.

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