Development of an enhanced scoring system to predict ICU readmission or in-hospital death within 24 hours using routine patient data from two NHS Foundation Trusts.

RATIONALE: Intensive care units (ICUs) admit the most severely ill patients. Once these patients are discharged from the ICU to a step-down ward, they continue to have their vital signs monitored by nursing staff, with Early Warning Score (EWS) systems being used to identify those at risk of deterioration. OBJECTIVES: We report the development and validation of an enhanced continuous scoring system for predicting adverse events, which combines vital signs measured routinely on acute care wards (as used by most EWS systems) with a risk score of a future adverse event calculated on discharge from the ICU. DESIGN: A modified Delphi process identified candidate variables commonly available in electronic records as the basis for a 'static' score of the patient's condition immediately after discharge from the ICU. L1-regularised logistic regression was used to estimate the in-hospital risk of future adverse event. We then constructed a model of physiological normality using vital sign data from the day of hospital discharge. This is combined with the static score and used continuously to quantify and update the patient's risk of deterioration throughout their hospital stay. SETTING: Data from two National Health Service Foundation Trusts (UK) were used to develop and (externally) validate the model. PARTICIPANTS: A total of 12 394 vital sign measurements were acquired from 273 patients after ICU discharge for the development set, and 4831 from 136 patients in the validation cohort. RESULTS: Outcome validation of our model yielded an area under the receiver operating characteristic curve of 0.724 for predicting ICU readmission or in-hospital death within 24 hours. It showed an improved performance with respect to other competitive risk scoring systems, including the National EWS (0.653). CONCLUSIONS: We showed that a scoring system incorporating data from a patient's stay in the ICU has better performance than commonly used EWS systems based on vital signs alone. TRIAL REGISTRATION NUMBER: ISRCTN32008295.

Self-supervised learning for human activity recognition using 700,000 person-days of wearable data.

Accurate physical activity monitoring is essential to understand the impact of physical activity on one's physical health and overall well-being. However, advances in human activity recognition algorithms have been constrained by the limited availability of large labelled datasets. This study aims to leverage recent advances in self-supervised learning to exploit the large-scale UK Biobank accelerometer dataset-a 700,000 person-days unlabelled dataset-in order to build models with vastly improved generalisability and accuracy. Our resulting models consistently outperform strong baselines across eight benchmark datasets, with an F1 relative improvement of 2.5-130.9% (median 24.4%). More importantly, in contrast to previous reports, our results generalise across external datasets, cohorts, living environments, and sensor devices. Our open-sourced pre-trained models will be valuable in domains with limited labelled data or where good sampling coverage (across devices, populations, and activities) is hard to achieve.

AZD1222 effectiveness against severe COVID-19 in individuals with comorbidity or frailty: The RAVEN cohort study.

OBJECTIVES: Despite being prioritized during initial COVID-19 vaccine rollout, vulnerable individuals at high risk of severe COVID-19 (hospitalization, intensive care unit admission, or death) remain underrepresented in vaccine effectiveness (VE) studies. The RAVEN cohort study (NCT05047822) assessed AZD1222 (ChAdOx1 nCov-19) two-dose primary series VE in vulnerable populations. METHODS: Using the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub, linked to secondary care, death registration, and COVID-19 datasets in England, COVID-19 outcomes in 2021 were compared in vaccinated and unvaccinated individuals matched on age, sex, region, and multimorbidity. RESULTS: Over 4.5 million AZD1222 recipients were matched (mean follow-up ∼5 months); 68% were ≥50 years, 57% had high multimorbidity. Overall, high VE against severe COVID-19 was demonstrated, with lower VE observed in vulnerable populations. VE against hospitalization was higher in the lowest multimorbidity quartile (91.1%; 95% CI: 90.1, 92.0) than the highest quartile (80.4%; 79.7, 81.1), and among individuals ≥65 years, higher in the 'fit' (86.2%; 84.5, 87.6) than the frailest (71.8%; 69.3, 74.2). VE against hospitalization was lowest in immunosuppressed individuals (64.6%; 60.7, 68.1). CONCLUSIONS: Based on integrated and comprehensive UK health data, overall population-level VE with AZD1222 was high. VEs were notably lower in vulnerable groups, particularly the immunosuppressed.

AutoNet-Generated Deep Layer-Wise Convex Networks for ECG Classification.

The design of neural networks typically involves trial-and-error, a time-consuming process for obtaining an optimal architecture, even for experienced researchers. Additionally, it is widely accepted that loss functions of deep neural networks are generally non-convex with respect to the parameters to be optimised. We propose the Layer-wise Convex Theorem to ensure that the loss is convex with respect to the parameters of a given layer, achieved by constraining each layer to be an overdetermined system of non-linear equations. Based on this theorem, we developed an end-to-end algorithm (the AutoNet) to automatically generate layer-wise convex networks (LCNs) for any given training set. We then demonstrate the performance of the AutoNet-generated LCNs (AutoNet-LCNs) compared to state-of-the-art models on three electrocardiogram (ECG) classification benchmark datasets, with further validation on two non-ECG benchmark datasets for more general tasks. The AutoNet-LCN was able to find networks customised for each dataset without manual fine-tuning under 2 GPU-hours, and the resulting networks outperformed the state-of-the-art models with fewer than 5% parameters on all the above five benchmark datasets. The efficiency and robustness of the AutoNet-LCN markedly reduce model discovery costs and enable efficient training of deep learning models in resource-constrained settings.

Digital health technologies and machine learning augment patient reported outcomes to remotely characterise rheumatoid arthritis.

Digital measures of health status captured during daily life could greatly augment current in-clinic assessments for rheumatoid arthritis (RA), to enable better assessment of disease progression and impact. This work presents results from weaRAble-PRO, a 14-day observational study, which aimed to investigate how digital health technologies (DHT), such as smartphones and wearables, could augment patient reported outcomes (PRO) to determine RA status and severity in a study of 30 moderate-to-severe RA patients, compared to 30 matched healthy controls (HC). Sensor-based measures of health status, mobility, dexterity, fatigue, and other RA specific symptoms were extracted from daily iPhone guided tests (GT), as well as actigraphy and heart rate sensor data, which was passively recorded from patients' Apple smartwatch continuously over the study duration. We subsequently developed a machine learning (ML) framework to distinguish RA status and to estimate RA severity. It was found that daily wearable sensor-outcomes robustly distinguished RA from HC participants (F1, 0.807). Furthermore, by day 7 of the study (half-way), a sufficient volume of data had been collected to reliably capture the characteristics of RA participants. In addition, we observed that the detection of RA severity levels could be improved by augmenting standard patient reported outcomes with sensor-based features (F1, 0.833) in comparison to using PRO assessments alone (F1, 0.759), and that the combination of modalities could reliability measure continuous RA severity, as determined by the clinician-assessed RAPID-3 score at baseline (r2, 0.692; RMSE, 1.33). The ability to measure the impact of the disease during daily life-through objective and remote digital outcomes-paves the way forward to enable the development of more patient-centric and personalised measurements for use in RA clinical trials.

ZeroNLG: Aligning and Autoencoding Domains for Zero-Shot Multimodal and Multilingual Natural Language Generation.

Natural Language Generation (NLG) accepts input data in the form of images, videos, or text and generates corresponding natural language text as output. Existing NLG methods mainly adopt a supervised approach and rely heavily on coupled data-to-text pairs. However, for many targeted scenarios and for non-English languages, sufficient quantities of labeled data are often not available. As a result, it is necessary to collect and label data-text pairs for training, which is both costly and time-consuming. To relax the dependency on labeled data of downstream tasks, we propose an intuitive and effective zero-shot learning framework, ZeroNLG, which can deal with multiple NLG tasks, including image-to-text (image captioning), video-to-text (video captioning), and text-to-text (neural machine translation), across English, Chinese, German, and French within a unified framework. ZeroNLG does not require any labeled downstream pairs for training. During training, ZeroNLG (i) projects different domains (across modalities and languages) to corresponding coordinates in a shared common latent space; (ii) bridges different domains by aligning their corresponding coordinates in this space; and (iii) builds an unsupervised multilingual auto-encoder to learn to generate text by reconstructing the input text given its coordinate in shared latent space. Consequently, during inference, based on the data-to-text pipeline, ZeroNLG can generate target sentences across different languages given the coordinate of input data in the common space. Within this unified framework, given visual (imaging or video) data as input, ZeroNLG can perform zero-shot visual captioning; given textual sentences as input, ZeroNLG can perform zero-shot machine translation. We present the results of extensive experiments on twelve NLG tasks, showing that, without using any labeled downstream pairs for training, ZeroNLG generates high-quality and "believable" outputs and significantly outperforms existing zero-shot methods. Our code and data are available at https://github.com/yangbang18/ZeroNLG.

Data encoding for healthcare data democratization and information leakage prevention.

The lack of data democratization and information leakage from trained models hinder the development and acceptance of robust deep learning-based healthcare solutions. This paper argues that irreversible data encoding can provide an effective solution to achieve data democratization without violating the privacy constraints imposed on healthcare data and clinical models. An ideal encoding framework transforms the data into a new space where it is imperceptible to a manual or computational inspection. However, encoded data should preserve the semantics of the original data such that deep learning models can be trained effectively. This paper hypothesizes the characteristics of the desired encoding framework and then exploits random projections and random quantum encoding to realize this framework for dense and longitudinal or time-series data. Experimental evaluation highlights that models trained on encoded time-series data effectively uphold the information bottleneck principle and hence, exhibit lesser information leakage from trained models.

Feasibility of wearable monitors to detect heart rate variability in children with hand, foot and mouth disease.

Hand foot and mouth disease (HFMD) is caused by a variety of enteroviruses, and occurs in large outbreaks in which a small proportion of children deteriorate rapidly with cardiopulmonary failure. Determining which children are likely to deteriorate is difficult and health systems may become overloaded during outbreaks as many children require hospitalization for monitoring. Heart rate variability (HRV) may help distinguish those with more severe diseases but requires simple scalable methods to collect ECG data.We carried out a prospective observational study to examine the feasibility of using wearable devices to measure HRV in 142 children admitted with HFMD at a children's hospital in Vietnam. ECG data were collected in all children. HRV indices calculated were lower in those with enterovirus A71 associated HFMD compared to those with other viral pathogens.HRV analysis collected from wearable devices is feasible in a low and middle income country (LMIC) and may help classify disease severity in HFMD.

A scalable federated learning solution for secondary care using low-cost microcomputing: privacy-preserving development and evaluation of a COVID-19 screening test in UK hospitals.

BACKGROUND: Multicentre training could reduce biases in medical artificial intelligence (AI); however, ethical, legal, and technical considerations can constrain the ability of hospitals to share data. Federated learning enables institutions to participate in algorithm development while retaining custody of their data but uptake in hospitals has been limited, possibly as deployment requires specialist software and technical expertise at each site. We previously developed an artificial intelligence-driven screening test for COVID-19 in emergency departments, known as CURIAL-Lab, which uses vital signs and blood tests that are routinely available within 1 h of a patient's arrival. Here we aimed to federate our COVID-19 screening test by developing an easy-to-use embedded system-which we introduce as full-stack federated learning-to train and evaluate machine learning models across four UK hospital groups without centralising patient data. METHODS: We supplied a Raspberry Pi 4 Model B preloaded with our federated learning software pipeline to four National Health Service (NHS) hospital groups in the UK: Oxford University Hospitals NHS Foundation Trust (OUH; through the locally linked research University, University of Oxford), University Hospitals Birmingham NHS Foundation Trust (UHB), Bedfordshire Hospitals NHS Foundation Trust (BH), and Portsmouth Hospitals University NHS Trust (PUH). OUH, PUH, and UHB participated in federated training, training a deep neural network and logistic regressor over 150 rounds to form and calibrate a global model to predict COVID-19 status, using clinical data from patients admitted before the pandemic (COVID-19-negative) and testing positive for COVID-19 during the first wave of the pandemic. We conducted a federated evaluation of the global model for admissions during the second wave of the pandemic at OUH, PUH, and externally at BH. For OUH and PUH, we additionally performed local fine-tuning of the global model using the sites' individual training data, forming a site-tuned model, and evaluated the resultant model for admissions during the second wave of the pandemic. This study included data collected between Dec 1, 2018, and March 1, 2021; the exact date ranges used varied by site. The primary outcome was overall model performance, measured as the area under the receiver operating characteristic curve (AUROC). Removable micro secure digital (microSD) storage was destroyed on study completion. FINDINGS: Clinical data from 130 941 patients (1772 COVID-19-positive), routinely collected across three hospital groups (OUH, PUH, and UHB), were included in federated training. The evaluation step included data from 32 986 patients (3549 COVID-19-positive) attending OUH, PUH, or BH during the second wave of the pandemic. Federated training of a global deep neural network classifier improved upon performance of models trained locally in terms of AUROC by a mean of 27·6% (SD 2·2): AUROC increased from 0·574 (95% CI 0·560-0·589) at OUH and 0·622 (0·608-0·637) at PUH using the locally trained models to 0·872 (0·862-0·882) at OUH and 0·876 (0·865-0·886) at PUH using the federated global model. Performance improvement was smaller for a logistic regression model, with a mean increase in AUROC of 13·9% (0·5%). During federated external evaluation at BH, AUROC for the global deep neural network model was 0·917 (0·893-0·942), with 89·7% sensitivity (83·6-93·6) and 76·6% specificity (73·9-79·1). Site-specific tuning of the global model did not significantly improve performance (change in AUROC <0·01). INTERPRETATION: We developed an embedded system for federated learning, using microcomputing to optimise for ease of deployment. We deployed full-stack federated learning across four UK hospital groups to develop a COVID-19 screening test without centralising patient data. Federation improved model performance, and the resultant global models were generalisable. Full-stack federated learning could enable hospitals to contribute to AI development at low cost and without specialist technical expertise at each site. FUNDING: The Wellcome Trust, University of Oxford Medical and Life Sciences Translational Fund.

Undertaking multi-centre randomised controlled trials in primary care: learnings and recommendations from the PULsE-AI trial researchers.

BACKGROUND: Conducting effective and translational research can be challenging and few trials undertake formal reflection exercises and disseminate learnings from them. Following completion of our multicentre randomised controlled trial, which was impacted by the COVID-19 pandemic, we sought to reflect on our experiences and share our thoughts on challenges, lessons learned, and recommendations for researchers undertaking or considering research in primary care. METHODS: Researchers involved in the Prediction of Undiagnosed atriaL fibrillation using a machinE learning AlgorIthm (PULsE-AI) trial, conducted in England from June 2019 to February 2021 were invited to participate in a qualitative reflection exercise. Members of the Trial Steering Committee (TSC) were invited to attend a semi-structured focus group session, Principal Investigators and their research teams at practices involved in the trial were invited to participate in a semi-structured interview. Following transcription, reflexive thematic analysis was undertaken based on pre-specified themes of recruitment, challenges, lessons learned, and recommendations that formed the structure of the focus group/interview sessions, whilst also allowing the exploration of new themes that emerged from the data. RESULTS: Eight of 14 members of the TSC, and one of six practices involved in the trial participated in the reflection exercise. Recruitment was highlighted as a major challenge encountered by trial researchers, even prior to disruption due to the COVID-19 pandemic. Researchers also commented on themes such as the need to consider incentivisation, and challenges associated with using technology in trials, especially in older age groups. CONCLUSIONS: Undertaking a formal reflection exercise following the completion of the PULsE-AI trial enabled us to review experiences encountered whilst undertaking a prospective randomised trial in primary care. In sharing our learnings, we hope to support other clinicians undertaking research in primary care to ensure that future trials are of optimal value for furthering knowledge, streamlining pathways, and benefitting patients.

Digital Health and Machine Learning Technologies for Blood Glucose Monitoring and Management of Gestational Diabetes.

Innovations in digital health and machine learning are changing the path of clinical health and care. People from different geographical locations and cultural backgrounds can benefit from the mobility of wearable devices and smartphones to monitor their health ubiquitously. This paper focuses on reviewing the digital health and machine learning technologies used in gestational diabetes - a subtype of diabetes that occurs during pregnancy. This paper reviews sensor technologies used in blood glucose monitoring devices, digital health innovations and machine learning models for gestational diabetes monitoring and management, in clinical and commercial settings, and discusses future directions. Despite one in six mothers having gestational diabetes, digital health applications were underdeveloped, especially the techniques that can be deployed in clinical practice. There is an urgent need to (1) develop clinically interpretable machine learning methods for patients with gestational diabetes, assisting health professionals with treatment, monitoring, and risk stratification before, during and after their pregnancies; (2) adapt and develop clinically-proven devices for patient self-management of health and well-being at home settings ("virtual ward" and virtual consultation), thereby improving clinical outcomes by facilitating timely intervention; and (3) ensure innovations are affordable and sustainable for all women with different socioeconomic backgrounds and clinical resources.

Uncertainties in the Analysis of Heart Rate Variability: A Systematic Review.

Heart rate variability (HRV) is an important metric with a variety of applications in clinical situations such as cardiovascular diseases, diabetes mellitus, and mental health. HRV data can be potentially obtained from electrocardiography and photoplethysmography signals, then computational techniques such as signal filtering and data segmentation are used to process the sampled data for calculating HRV measures. However, uncertainties arising from data acquisition, computational models, and physiological factors can lead to degraded signal quality and affect HRV analysis. Therefore, it is crucial to address these uncertainties and develop advanced models for HRV analysis. Although several reviews of HRV analysis exist, they primarily focus on clinical applications, trends in HRV methods, or specific aspects of uncertainties such as measurement noise. This paper provides a comprehensive review of uncertainties in HRV analysis, quantifies their impacts, and outlines potential solutions. To the best of our knowledge, this is the first study that presents a holistic review of uncertainties in HRV methods and quantifies their impacts on HRV measures from an engineer's perspective. This review is essential for developing robust and reliable models, and could serve as a valuable future reference in the field, particularly for dealing with uncertainties in HRV analysis.

Heart Rate Variability Measured from Wearable Devices as a Marker of Disease Severity in Tetanus.

Tetanus is a disease associated with significant morbidity and mortality. Heart rate variability (HRV) is an objective clinical marker with potential value in tetanus. This study aimed to investigate the use of wearable devices to collect HRV data and the relationship between HRV and tetanus severity. Data were collected from 110 patients admitted to the intensive care unit in a tertiary hospital in Vietnam. HRV indices were calculated from 5-minute segments of 24-hour electrocardiogram recordings collected using wearable devices. HRV was found to be inversely related to disease severity. The standard deviation of NN intervals and interquartile range of RR intervals (IRRR) were significantly associated with the presence of muscle spasms; low frequency (LF) and high frequency (HF) indices were significantly associated with severe respiratory compromise; and the standard deviation of differences between adjacent NN intervals, root mean square of successive differences between normal heartbeats, LF to HF ratio, total frequency power, and IRRR, were significantly associated with autonomic nervous system dysfunction. The findings support the potential value of HRV as a marker for tetanus severity, identifying specific indices associated with clinical severity thresholds. Data were recorded using wearable devices, demonstrating this approach in resource-limited settings where most tetanus occurs.

Intelligent Electrocardiogram Acquisition Via Ubiquitous Photoplethysmography Monitoring.

Recent advances in machine learning, particularly deep neural network architectures, have shown substantial promise in classifying and predicting cardiac abnormalities from electrocardiogram (ECG) data. Such data are rich in information content, typically in morphology and timing, due to the close correlation between cardiac function and the ECG. However, the ECG is usually not measured ubiquitously in a passive manner from consumer devices, and generally requires 'active' sampling whereby the user prompts a device to take an ECG measurement. Conversely, photoplethysmography (PPG) data are typically measured passively by consumer devices, and therefore available for long-period monitoring and suitable in duration for identifying transient cardiac events. However, classifying or predicting cardiac abnormalities from the PPG is very difficult, because it is a peripherally-measured signal. Hence, the use of the PPG for predictive inference is often limited to deriving physiological parameters (heart rate, breathing rate, etc.) or for obvious abnormalities in cardiac timing, such as atrial fibrillation/flutter ("palpitations"). This work aims to combine the best of both worlds: using continuously-monitored, near-ubiquitous PPG to identify periods of sufficient abnormality in the PPG such that prompting the user to take an ECG would be informative of cardiac risk. We propose a dual-convolutional-attention network (DCA-Net) to achieve this ECG-based PPG classification. With DCA-Net, we prove the plausibility of this concept on MIMIC Waveform Database with high performance level (AUROC 0.9 and AUPRC 0.7) and receive satisfactory result when testing the model on an independent dataset (AUROC 0.7 and AUPRC 0.6) which it is not perfectly-matched to the MIMIC dataset.

DuKA: A Dual-Keyless-Attention Model for Multi-modality EHR Data Fusion and Organ Failure Prediction.

OBJECTIVE: Organ failure is a leading cause of mortality in hospitals, particularly in intensive care units. Predicting organ failure is crucial for clinical and social reasons. This study proposes a dual-keyless-attention (DuKA) model that enables interpretable predictions of organ failure using electronic health record (EHR) data. METHODS: Three modalities of medical data from EHR, namely diagnosis, procedure, and medications, are selected to predict three types of vital organ failures: heart failure, respiratory failure, and kidney failure. DuKA utilizes pre-trained embeddings of medical codes and combines them using a modality-wise attention module and a medical concept-wise attention module to enhance interpretation. Three organ failure tasks are addressed using two datasets to verify the effectiveness of DuKA. RESULTS: The proposed multi-modality DuKA model outperforms all reference and baseline models. The diagnosis history, particularly the presence of cachexia and previous organ failure, emerges as the most influential feature in organ failure prediction. CONCLUSIONS: DuKA offers competitive performance, straightforward model interpretations and flexibility in terms of input sources, as the input embeddings can be trained using different datasets and methods. SIGNIFICANCE: DuKA is a lightweight model that innovatively uses dual attention in a hierarchical way to fuse diagnosis, procedure and medication information for organ failure predictions. It also enhances disease comprehension and supports personalized treatment.

A medical multimodal large language model for future pandemics.

Deep neural networks have been integrated into the whole clinical decision procedure which can improve the efficiency of diagnosis and alleviate the heavy workload of physicians. Since most neural networks are supervised, their performance heavily depends on the volume and quality of available labels. However, few such labels exist for rare diseases (e.g., new pandemics). Here we report a medical multimodal large language model (Med-MLLM) for radiograph representation learning, which can learn broad medical knowledge (e.g., image understanding, text semantics, and clinical phenotypes) from unlabelled data. As a result, when encountering a rare disease, our Med-MLLM can be rapidly deployed and easily adapted to them with limited labels. Furthermore, our model supports medical data across visual modality (e.g., chest X-ray and CT) and textual modality (e.g., medical report and free-text clinical note); therefore, it can be used for clinical tasks that involve both visual and textual data. We demonstrate the effectiveness of our Med-MLLM by showing how it would perform using the COVID-19 pandemic "in replay". In the retrospective setting, we test the model on the early COVID-19 datasets; and in the prospective setting, we test the model on the new variant COVID-19-Omicron. The experiments are conducted on 1) three kinds of input data; 2) three kinds of downstream tasks, including disease reporting, diagnosis, and prognosis; 3) five COVID-19 datasets; and 4) three different languages, including English, Chinese, and Spanish. All experiments show that our model can make accurate and robust COVID-19 decision-support with little labelled data.

Semi-Supervised Learning for Multi-Label Cardiovascular Diseases Prediction: A Multi-Dataset Study.

Electrocardiography (ECG) is a non-invasive tool for predicting cardiovascular diseases (CVDs). Current ECG-based diagnosis systems show promising performance owing to the rapid development of deep learning techniques. However, the label scarcity problem, the co-occurrence of multiple CVDs and the poor performance on unseen datasets greatly hinder the widespread application of deep learning-based models. Addressing them in a unified framework remains a significant challenge. To this end, we propose a multi-label semi-supervised model (ECGMatch) to recognize multiple CVDs simultaneously with limited supervision. In the ECGMatch, an ECGAugment module is developed for weak and strong ECG data augmentation, which generates diverse samples for model training. Subsequently, a hyperparameter-efficient framework with neighbor agreement modeling and knowledge distillation is designed for pseudo-label generation and refinement, which mitigates the label scarcity problem. Finally, a label correlation alignment module is proposed to capture the co-occurrence information of different CVDs within labeled samples and propagate this information to unlabeled samples. Extensive experiments on four datasets and three protocols demonstrate the effectiveness and stability of the proposed model, especially on unseen datasets. As such, this model can pave the way for diagnostic systems that achieve robust performance on multi-label CVDs prediction with limited supervision. Code is available at https://github.com/KAZABANA/ECGMatch.

Development and implementation of optimized endogenous contrast sequences for delineation in adaptive radiotherapy on a 1.5T MR-linear-accelerator: a prospective R-IDEAL stage 0-2a quantitative/qualitative evaluation of in vivo site-specific quality-assurance using a 3D T2 fat-suppressed platform for head and neck cancer.

Purpose: To improve segmentation accuracy in head and neck cancer (HNC) radiotherapy treatment planning for the 1.5T hybrid magnetic resonance imaging/linear accelerator (MR-Linac), three-dimensional (3D), T2-weighted, fat-suppressed magnetic resonance imaging sequences were developed and optimized. Approach: After initial testing, spectral attenuated inversion recovery (SPAIR) was chosen as the fat suppression technique. Five candidate SPAIR sequences and a nonsuppressed, T2-weighted sequence were acquired for five HNC patients using a 1.5T MR-Linac. MR physicists identified persistent artifacts in two of the SPAIR sequences, so the remaining three SPAIR sequences were further analyzed. The gross primary tumor volume, metastatic lymph nodes, parotid glands, and pterygoid muscles were delineated using five segmentors. A robust image quality analysis platform was developed to objectively score the SPAIR sequences on the basis of qualitative and quantitative metrics. Results: Sequences were analyzed for the signal-to-noise ratio and the contrast-to-noise ratio and compared with fat and muscle, conspicuity, pairwise distance metrics, and segmentor assessments. In this analysis, the nonsuppressed sequence was inferior to each of the SPAIR sequences for the primary tumor, lymph nodes, and parotid glands, but it was superior for the pterygoid muscles. The SPAIR sequence that received the highest combined score among the analysis categories was recommended to Unity MR-Linac users for HNC radiotherapy treatment planning. Conclusions: Our study led to two developments: an optimized, 3D, T2-weighted, fat-suppressed sequence that can be disseminated to Unity MR-Linac users and a robust image quality analysis pathway that can be used to objectively score SPAIR sequences and can be customized and generalized to any image quality optimization protocol. Improved segmentation accuracy with the proposed SPAIR sequence will potentially lead to improved treatment outcomes and reduced toxicity for patients by maximizing the target coverage and minimizing the radiation exposure of organs at risk.

Prevalence and implications of significance testing for baseline covariate imbalance in randomised cancer clinical trials: The Table 1 Fallacy.

BACKGROUND: The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials. METHODS: From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy. RESULTS: A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18-0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19-0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03-0.13; multiplicity-corrected P < 0.0001). CONCLUSIONS: This study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy.