Early detection of disease outbreaks and non-outbreaks using incidence data

Forecasting the occurrence and absence of novel disease outbreaks is essential for disease management. Here, we develop a general model, with no real-world training data, that accurately forecasts outbreaks and non-outbreaks. We propose a novel framework, using a feature-based time series classification method to forecast outbreaks and non-outbreaks. We tested our methods on synthetic data from a Susceptible-Infected-Recovered model for slowly changing, noisy disease dynamics. Outbreak sequences give a transcritical bifurcation within a specified future time window, whereas non-outbreak (null bifurcation) sequences do not. We identified incipient differences in time series of infectives leading to future outbreaks and non-outbreaks. These differences are reflected in 22 statistical features and 5 early warning signal indicators. Classifier performance, given by the area under the receiver-operating curve, ranged from 0.99 for large expanding windows of training data to 0.7 for small rolling windows. Real-world performances of classifiers were tested on two empirical datasets, COVID-19 data from Singapore and SARS data from Hong Kong, with two classifiers exhibiting high accuracy. In summary, we showed that there are statistical features that distinguish outbreak and non-outbreak sequences long before outbreaks occur. We could detect these differences in synthetic and real-world data sets, well before potential outbreaks occur.

An early warning indicator trained on stochastic disease-spreading models with different noises

The timely detection of disease outbreaks through reliable early warning signals (EWSs) is indispensable for effective public health mitigation strategies. Nevertheless, the intricate dynamics of real-world disease spread, often influenced by diverse sources of noise and limited data in the early stages of outbreaks, pose a significant challenge in developing reliable EWSs, as the performance of existing indicators varies with extrinsic and intrinsic noises. Here, we address the challenge of modeling disease when the measurements are corrupted by additive white noise, multiplicative environmental noise, and demographic noise into a standard epidemic mathematical model. To navigate the complexities introduced by these noise sources, we employ a deep learning algorithm that provides EWS in infectious disease outbreak by training on noise-induced disease-spreading models. The indicator's effectiveness is demonstrated through its application to real-world COVID-19 cases in Edmonton and simulated time series derived from diverse disease spread models affected by noise. Notably, the indicator captures an impending transition in a time series of disease outbreaks and outperforms existing indicators. This study contributes to advancing early warning capabilities by addressing the intricate dynamics inherent in real-world disease spread, presenting a promising avenue for enhancing public health preparedness and response efforts.

Copula-Based Deep Survival Models for Dependent Censoring

A survival dataset describes a set of instances (e.g. patients) and provides, for each, either the time until an event (e.g. death), or the censoring time (e.g. when lost to follow-up - which is a lower bound on the time until the event). We consider the challenge of survival prediction: learning, from such data, a predictive model that can produce an individual survival distribution for a novel instance. Many contemporary methods of survival prediction implicitly assume that the event and censoring distributions are independent conditional on the instance's covariates - a strong assumption that is difficult to verify (as we observe only one outcome for each instance) and which can induce significant bias when it does not hold. This paper presents a parametric model of survival that extends modern non-linear survival analysis by relaxing the assumption of conditional independence. On synthetic and semi-synthetic data, our approach significantly improves estimates of survival distributions compared to the standard that assumes conditional independence in the data.

An Effective Meaningful Way to Evaluate Survival Models

One straightforward metric to evaluate a survival prediction model is based on the Mean Absolute Error (MAE) -- the average of the absolute difference between the time predicted by the model and the true event time, over all subjects. Unfortunately, this is challenging because, in practice, the test set includes (right) censored individuals, meaning we do not know when a censored individual actually experienced the event. In this paper, we explore various metrics to estimate MAE for survival datasets that include (many) censored individuals. Moreover, we introduce a novel and effective approach for generating realistic semi-synthetic survival datasets to facilitate the evaluation of metrics. Our findings, based on the analysis of the semi-synthetic datasets, reveal that our proposed metric (MAE using pseudo-observations) is able to rank models accurately based on their performance, and often closely matches the true MAE -- in particular, is better than several alternative methods.

The ACROBAT 2022 Challenge: Automatic Registration Of Breast Cancer Tissue

The alignment of tissue between histopathological whole-slide-images (WSI) is crucial for research and clinical applications. Advances in computing, deep learning, and availability of large WSI datasets have revolutionised WSI analysis. Therefore, the current state-of-the-art in WSI registration is unclear. To address this, we conducted the ACROBAT challenge, based on the largest WSI registration dataset to date, including 4,212 WSIs from 1,152 breast cancer patients. The challenge objective was to align WSIs of tissue that was stained with routine diagnostic immunohistochemistry to its H&E-stained counterpart. We compare the performance of eight WSI registration algorithms, including an investigation of the impact of different WSI properties and clinical covariates. We find that conceptually distinct WSI registration methods can lead to highly accurate registration performances and identify covariates that impact performances across methods. These results establish the current state-of-the-art in WSI registration and guide researchers in selecting and developing methods.

Modeling and Forecasting COVID-19 Cases using Latent Subpopulations

Classical epidemiological models assume homogeneous populations. There have been important extensions to model heterogeneous populations, when the identity of the sub-populations is known, such as age group or geographical location. Here, we propose two new methods to model the number of people infected with COVID-19 over time, each as a linear combination of latent sub-populations -- i.e., when we do not know which person is in which sub-population, and the only available observations are the aggregates across all sub-populations. Method #1 is a dictionary-based approach, which begins with a large number of pre-defined sub-population models (each with its own starting time, shape, etc), then determines the (positive) weight of small (learned) number of sub-populations. Method #2 is a mixture-of-$M$ fittable curves, where $M$, the number of sub-populations to use, is given by the user. Both methods are compatible with any parametric model; here we demonstrate their use with first (a)~Gaussian curves and then (b)~SIR trajectories. We empirically show the performance of the proposed methods, first in (i) modeling the observed data and then in (ii) forecasting the number of infected people 1 to 4 weeks in advance. Across 187 countries, we show that the dictionary approach had the lowest mean absolute percentage error and also the lowest variance when compared with classical SIR models and moreover, it was a strong baseline that outperforms many of the models developed for COVID-19 forecasting.

Improving ECG-based COVID-19 diagnosis and mortality predictions using pre-pandemic medical records at population-scale

Pandemic outbreaks such as COVID-19 occur unexpectedly, and need immediate action due to their potential devastating consequences on global health. Point-of-care routine assessments such as electrocardiogram (ECG), can be used to develop prediction models for identifying individuals at risk. However, there is often too little clinically-annotated medical data, especially in early phases of a pandemic, to develop accurate prediction models. In such situations, historical pre-pandemic health records can be utilized to estimate a preliminary model, which can then be fine-tuned based on limited available pandemic data. This study shows this approach -- pre-train deep learning models with pre-pandemic data -- can work effectively, by demonstrating substantial performance improvement over three different COVID-19 related diagnostic and prognostic prediction tasks. Similar transfer learning strategies can be useful for developing timely artificial intelligence solutions in future pandemic outbreaks.

ECG for high-throughput screening of multiple diseases: Proof-of-concept using multi-diagnosis deep learning from population-based datasets

Electrocardiogram (ECG) abnormalities are linked to cardiovascular diseases, but may also occur in other non-cardiovascular conditions such as mental, neurological, metabolic and infectious conditions. However, most of the recent success of deep learning (DL) based diagnostic predictions in selected patient cohorts have been limited to a small set of cardiac diseases. In this study, we use a population-based dataset of >250,000 patients with >1000 medical conditions and >2 million ECGs to identify a wide range of diseases that could be accurately diagnosed from the patient's first in-hospital ECG. Our DL models uncovered 128 diseases and 68 disease categories with strong discriminative performance.

Domain-shift adaptation via linear transformations

A predictor, $f_A : X \to Y$, learned with data from a source domain (A) might not be accurate on a target domain (B) when their distributions are different. Domain adaptation aims to reduce the negative effects of this distribution mismatch. Here, we analyze the case where $P_A(Y\ |\ X) \neq P_B(Y\ |\ X)$, $P_A(X) \neq P_B(X)$ but $P_A(Y) = P_B(Y)$; where there are affine transformations of $X$ that makes all distributions equivalent. We propose an approach to project the source and target domains into a lower-dimensional, common space, by (1) projecting the domains into the eigenvectors of the empirical covariance matrices of each domain, then (2) finding an orthogonal matrix that minimizes the maximum mean discrepancy between the projections of both domains. For arbitrary affine transformations, there is an inherent unidentifiability problem when performing unsupervised domain adaptation that can be alleviated in the semi-supervised case. We show the effectiveness of our approach in simulated data and in binary digit classification tasks, obtaining improvements up to 48% accuracy when correcting for the domain shift in the data.

Variational Auto-Encoder Architectures that Excel at Causal Inference

Estimating causal effects from observational data (at either an individual -- or a population -- level) is critical for making many types of decisions. One approach to address this task is to learn decomposed representations of the underlying factors of data; this becomes significantly more challenging when there are confounding factors (which influence both the cause and the effect). In this paper, we take a generative approach that builds on the recent advances in Variational Auto-Encoders to simultaneously learn those underlying factors as well as the causal effects. We propose a progressive sequence of models, where each improves over the previous one, culminating in the Hybrid model. Our empirical results demonstrate that the performance of all three proposed models are superior to both state-of-the-art discriminative as well as other generative approaches in the literature.