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One major impediment to the wider use of deep learning for clinical decision making is the difficulty of assigning a level of confidence to model predictions. Currently, deep Bayesian neural networks and sparse Gaussian processes are the main two scalable uncertainty estimation methods. However, deep Bayesian neural networks suffer from lack of expressiveness, and more expressive models such as deep kernel learning, which is an extension of sparse Gaussian process, captures only the uncertainty from the higher-level latent space. Therefore, the deep learning model under it lacks interpretability and ignores uncertainty from the raw data. In this paper, we merge features of the deep Bayesian learning framework with deep kernel learning to leverage the strengths of both methods for a more comprehensive uncertainty estimation. Through a series of experiments on predicting the first incidence of heart failure, diabetes and depression applied to large-scale electronic medical records, we demonstrate that our method is better at capturing uncertainty than both Gaussian processes and deep Bayesian neural networks in terms of indicating data insufficiency and identifying misclassifications, with a comparable generalization performance. Furthermore, by assessing the accuracy and area under the receiver operating characteristic curve over the predictive probability, we show that our method is less susceptible to making overconfident predictions, especially for the minority class in imbalanced datasets. Finally, we demonstrate how uncertainty information derived by the model can inform risk factor analysis towards model interpretability.

Today, despite decades of developments in medicine and the growing interest in precision healthcare, vast majority of diagnoses happen once patients begin to show noticeable signs of illness. Early indication and detection of diseases, however, can provide patients and carers with the chance of early intervention, better disease management, and efficient allocation of healthcare resources. The latest developments in machine learning (including deep learning) provides a great opportunity to address this unmet need. In this study, we introduce BEHRT: A deep neural sequence transduction model for electronic health records (EHR), capable of simultaneously predicting the likelihood of 301 conditions in one’s future visits. When trained and evaluated on the data from nearly 1.6 million individuals, BEHRT shows a striking improvement of 8.0–13.2% (in terms of average precision scores for different tasks), over the existing state-of-the-art deep EHR models. In addition to its scalability and superior accuracy, BEHRT enables personalised interpretation of its predictions; its flexible architecture enables it to incorporate multiple heterogeneous concepts (e.g., diagnosis, medication, measurements, and more) to further improve the accuracy of its predictions; its (pre-)training results in disease and patient representations can be useful for future studies (i.e., transfer learning).

Many sources of fluctuation contribute to the fMRI signal, and this makes identifying the effects that are truly related to the underlying neuronal activity difficult. Independent component analysis (ICA) – one of the most widely used techniques for the exploratory analysis of fMRI data – has shown to be a powerful technique in identifying various sources of neuronally-related and artefactual fluctuation in fMRI data (both with the application of external stimuli and with the subject “at rest”). ICA decomposes fMRI data into patterns of activity (a set of spatial maps and their corresponding time series) that are statistically independent and add linearly to explain voxel-wise time series. Given the set of ICA components, if the components representing “signal” (brain activity) can be distinguished form the “noise” components (effects of motion, non-neuronal physiology, scanner artefacts and other nuisance sources), the latter can then be removed from the data, providing an effective cleanup of structured noise. Manual classification of components is labour intensive and requires expertise; hence, a fully automatic noise detection algorithm that can reliably detect various types of noise sources (in both task and resting fMRI) is desirable. In this paper, we introduce FIX (“FMRIB's ICA-based X-noiseifier”), which provides an automatic solution for denoising fMRI data via accurate classification of ICA components. For each ICA component FIX generates a large number of distinct spatial and temporal features, each describing a different aspect of the data (e.g., what proportion of temporal fluctuations are at high frequencies). The set of features is then fed into a multi-level classifier (built around several different classifiers). Once trained through the hand-classification of a sufficient number of training datasets, the classifier can then automatically classify new datasets. The noise components can then be subtracted from (or regressed out of) the original data, to provide automated cleanup. On conventional resting-state fMRI (rfMRI) single-run datasets, FIX achieved about 95% overall accuracy. On high-quality rfMRI data from the Human Connectome Project, FIX achieves over 99% classification accuracy, and as a result is being used in the default rfMRI processing pipeline for generating HCP connectomes. FIX is publicly available as a plugin for FSL.

Emergency admissions are a major source of healthcare spending. We aimed to derive, validate, and compare conventional and machine learning models for prediction of the first emergency admission. Machine learning methods are capable of capturing complex interactions that are likely to be present when predicting less specific outcomes, such as this one. We used longitudinal data from linked electronic health records of 4.6 million patients aged 18-100 years from 389 practices across England between 1985 to 2015. The population was divided into a derivation cohort (80%, 3.75 million patients from 300 general practices) and a validation cohort (20%, 0.88 million patients from 89 general practices) from geographically distinct regions with different risk levels. We first replicated a previously reported Cox proportional hazards (CPH) model for prediction of the risk of the first emergency admission up to 24 months after baseline. This reference model was then compared with 2 machine learning models, random forest (RF) and gradient boosting classifier (GBC). The initial set of predictors for all models included 43 variables, including patient demographics, lifestyle factors, laboratory tests, currently prescribed medications, selected morbidities, and previous emergency admissions. We then added 13 more variables (marital status, prior general practice visits, and 11 additional morbidities), and also enriched all variables by incorporating temporal information whenever possible (e.g., time since first diagnosis). We also varied the prediction windows to 12, 36, 48, and 60 months after baseline and compared model performances. For internal validation, we used 5-fold cross-validation. When the initial set of variables was used, GBC outperformed RF and CPH, with an area under the receiver operating characteristic curve (AUC) of 0.779 (95% CI 0.777, 0.781), compared to 0.752 (95% CI 0.751, 0.753) and 0.740 (95% CI 0.739, 0.741), respectively. In external validation, we observed an AUC of 0.796, 0.736, and 0.736 for GBC, RF, and CPH, respectively. The addition of temporal information improved AUC across all models. In internal validation, the AUC rose to 0.848 (95% CI 0.847, 0.849), 0.825 (95% CI 0.824, 0.826), and 0.805 (95% CI 0.804, 0.806) for GBC, RF, and CPH, respectively, while the AUC in external validation rose to 0.826, 0.810, and 0.788, respectively. This enhancement also resulted in robust predictions for longer time horizons, with AUC values remaining at similar levels across all models. Overall, compared to the baseline reference CPH model, the final GBC model showed a 10.8% higher AUC (0.848 compared to 0.740) for prediction of risk of emergency admission within 24 months. GBC also showed the best calibration throughout the risk spectrum. Despite the wide range of variables included in models, our study was still limited by the number of variables included; inclusion of more variables could have further improved model performances. The use of machine learning and addition of temporal information led to substantially improved discrimination and calibration for predicting the risk of emergency admission. Model performance remained stable across a range of prediction time windows and when externally validated. These findings support the potential of incorporating machine learning models into electronic health records to inform care and service planning.

Background Myocardial infarction (MI), stroke and diabetes share underlying risk factors and commonalities in clinical management. We examined if their combined impact on mortality is proportional, amplified or less than the expected risk separately of each disease and whether the excess risk is explained by their associated comorbidities. Methods Using large-scale electronic health records, we identified 2,007,731 eligible patients (51% women) and registered with general practices in the UK and extracted clinical information including diagnosis of myocardial infarction (MI), stroke, diabetes and 53 other long-term conditions before 2005 (study baseline). We used Cox regression to determine the risk of all-cause mortality with age as the underlying time variable and tested for excess risk due to interaction between cardiometabolic conditions. Results At baseline, the mean age was 51 years, and 7% ( N = 145,910) have had a cardiometabolic condition. After a 7-year mean follow-up, 146,994 died. The sex-adjusted hazard ratios ( HR ) (95% confidence interval [ CI ]) of all-cause mortality by baseline disease status, compared to those without cardiometabolic disease, were MI = 1.51 (1.49–1.52), diabetes = 1.52 (1.51–1.53), stroke = 1.84 (1.82–1.86), MI and diabetes = 2.14 (2.11–2.17), MI and stroke = 2.35 (2.30–2.39), diabetes and stroke = 2.53 (2.50–2.57) and all three = 3.22 (3.15–3.30). Adjusting for other concurrent comorbidities attenuated these estimates, including the risk associated with having all three conditions ( HR = 1.81 [ 95% CI 1.74–1.89]). Excess risks due to interaction between cardiometabolic conditions, particularly when all three conditions were present, were not significantly greater than expected from the individual disease effects. Conclusion Myocardial infarction, stroke and diabetes were associated with excess mortality, without evidence of any amplification of risk in people with all three diseases. The presence of other comorbidities substantially contributed to the excess mortality risks associated with cardiometabolic disease multimorbidity.

In nonstationary images, cluster inference depends on the local image smoothness, as clusters tend to be larger in smoother regions by chance alone. In order to correct the inference for such nonstationary, cluster sizes can be adjusted according to a local smoothness estimate. In this study, adjusted cluster sizes are used in a permutation-testing framework for both cluster-based and threshold-free cluster enhancement (TFCE) inference and tested on both simulated and real data. We find that TFCE inference is already fairly robust to nonstationarity in the data, while cluster-based inference requires an adjustment to ensure homogeneity. A group of possible multi-level adjustments are introduced and their results on simulated and real data are assessed using a new performance index. We also find that adjusting for local smoothness via a separate resampling procedure is more effective at removing nonstationarity than an adjustment via a random field theory based smoothness estimator. ► In this paper adjusted cluster sizes are used in a permutation-testing framework for both cluster-based and threshold-free cluster enhancement (TFCE) inference and tested on both simulated and real data. ► We find TFCE inference is already fairly robust to nonstationarity in the data, while cluster-based inference requires an adjustment to ensure homogeneity. ► A group of possible multi-level adjustments are introduced and their results on simulated and real data are assessed using a new performance index. ► We also find that adjusting for local smoothness via a local estimation of a statistic’s null distribution (from a first pass through the permutation testing) is more effective at removing nonstationarity than correction via local smoothness estimation.

Multicollinearity refers to the presence of collinearity between multiple variables and renders the results of statistical inference erroneous (Type II error). This is particularly important in environmental health research where multicollinearity can hinder inference. To address this, correlated variables are often excluded from the analysis, limiting the discovery of new associations. An alternative approach to address this problem is the use of principal component analysis. This method, combines and projects a group of correlated variables onto a new orthogonal space. While this resolves the multicollinearity problem, it poses another challenge in relation to interpretability of results. Standard hypothesis testing methods can be used to evaluate the association of projected predictors, called principal components, with the outcomes of interest, however, there is no established way to trace the significance of principal components back to individual variables. To address this problem, we investigated the use of sparse principal component analysis which enforces a parsimonious projection. We hypothesise that this parsimony could facilitate the interpretability of findings. To this end, we investigated the association of 20 environmental predictors with all-cause mortality adjusting for demographic, socioeconomic, physiological, and behavioural factors. The study was conducted in a cohort of 379,690 individuals in the UK. During an average follow-up of 8.05 years (3,055,166 total person-years), 14,996 deaths were observed. We used Cox regression models to estimate the hazard ratio (HR) and 95% confidence intervals (CI). The Cox models were fitted to the standardised environmental predictors (a) without any transformation (b) transformed with PCA, and (c) transformed with SPCA. The comparison of findings underlined the potential of SPCA for conducting inference in scenarios where multicollinearity can increase the risk of Type II error. Our analysis unravelled a significant association between average noise pollution and increased risk of all-cause mortality. Specifically, those in the upper deciles of noise exposure have between 5 and 10% increased risk of all-cause mortality compared to the lowest decile.

With the rapid growth of neuroimaging research and accumulation of neuroinformatic databases the synthesis of consensus findings using meta-analysis is becoming increasingly important. Meta-analyses pool data across many studies to identify reliable experimental effects and characterize the degree of agreement across studies. Coordinate-based meta-analysis (CBMA) methods are the standard approach, where each study entered into the meta-analysis has been summarized using only the (x, y, z) locations of peak activations (with or without activation magnitude) reported in published reports. Image-based meta-analysis (IBMA) methods use the full statistic images, and allow the use of hierarchical mixed effects models that account for differing intra-study variance and modeling of random inter-study variation. The purpose of this work is to compare image-based and coordinate-based meta-analysis methods applied to the same dataset, a group of 15 fMRI studies of pain, and to quantify the information lost by working only with the coordinates of peak activations instead of the full statistic images. We apply a 3-level IBMA mixed model for a \"mega-analysis\", and highlight important considerations in the specification of each model and contrast. We compare the IBMA result to three CBMA methods: ALE (activation likelihood estimation), KDA (kernel density analysis) and MKDA (multi-level kernel density analysis), for various CBMA smoothing parameters. For the datasets considered, we find that ALE at σ=15 mm, KDA at ρ=25–30 mm and MKDA at ρ=15 mm give the greatest similarity to the IBMA result, and that ALE was the most similar for this particular dataset, though only with a Dice similarity coefficient of 0.45 (Dice measure ranges from 0 to 1). Based on this poor similarity, and the greater modeling flexibility afforded by hierarchical mixed models, we suggest that IBMA is preferred over CBMA. To make IBMA analyses practical, however, the neuroimaging field needs to develop an effective mechanism for sharing image data, including whole-brain images of both effect estimates and their standard errors.

Over a billion people live in slums, with poor sanitation, education, property rights and working conditions having a direct impact on current residents and future generations. Slum mapping is one of the key problems concerning slums. Policymakers need to delineate slum settlements to make informed decisions about infrastructure development and allocation of aid. A wide variety of machine learning and deep learning methods have been applied to multispectral satellite images to map slums with outstanding performance. Since the physical and visual manifestation of slums significantly varies with geographical region and comprehensive slum maps are rare, it is important to quantify the uncertainty of predictions for reliable and confident application of models to downstream tasks. In this study, we train a U-Net model with Monte Carlo Dropout (MCD) on 13-band Sentinel-2 images, allowing us to calculate pixelwise uncertainty in the predictions. The obtained outcomes show that the proposed model outperforms the previous state-of-the-art model, having both higher AUPRC and lower uncertainty when tested on unseen geographical regions of Mumbai using the regional testing framework introduced in this study. We also use SHapley Additive exPlanations (SHAP) values to investigate how the different features contribute to our model’s predictions which indicate a certain shortwave infrared image band is a powerful feature for determining the locations of slums within images. With our results, we demonstrate the usefulness of including an uncertainty quantification approach in detecting slum area changes over time.