MOTIVATION: Acute kidney injury (AKI) is a syndrome that affects a large fraction of all critically ill patients, and early diagnosis to receive adequate treatment is as imperative as it is challenging to make early. Consequently, machine learning approaches have been developed to predict AKI ahead of time. However, the prevalence of AKI is often underestimated in state-of-the-art approaches, as they rely on an AKI event annotation solely based on creatinine, ignoring urine output. We construct and evaluate early warning systems for AKI in a multi-disciplinary ICU setting, using the complete KDIGO definition of AKI. We propose several variants of gradient-boosted decision tree (GBDT)-based models, including a novel time-stacking based approach. A state-of-the-art LSTM-based model previously proposed for AKI prediction is used as a comparison, which was not specifically evaluated in ICU settings yet. RESULTS: We find that optimal performance is achieved by using GBDT with the time-based stacking technique (AUPRC = 65.7%, compared with the LSTM-based model's AUPRC = 62.6%), which is motivated by the high relevance of time since ICU admission for this task. Both models show mildly reduced performance in the limited training data setting, perform fairly across different subcohorts, and exhibit no issues in gender transfer. Following the official KDIGO definition substantially increases the number of annotated AKI events. In our study GBDTs outperform LSTM models for AKI prediction. Generally, we find that both model types are robust in a variety of challenging settings arising for ICU data. AVAILABILITY AND IMPLEMENTATION: The code to reproduce the findings of our manuscript can be found at: https://github.com/ratschlab/AKI-EWS.

MOTIVATION: Temporal biomarker discovery in longitudinal data is based on detecting reoccurring trajectories, the so-called shapelets. The search for shapelets requires considering all subsequences in the data. While the accompanying issue of multiple testing has been mitigated in previous work, the redundancy and overlap of the detected shapelets results in an a priori unbounded number of highly similar and structurally meaningless shapelets. As a consequence, current temporal biomarker discovery methods are impractical and underpowered. RESULTS: We find that the pre- or post-processing of shapelets does not sufficiently increase the power and practical utility. Consequently, we present a novel method for temporal biomarker discovery: Statistically Significant Submodular Subset Shapelet Mining (S5M) that retrieves short subsequences that are (i) occurring in the data, (ii) are statistically significantly associated with the phenotype and (iii) are of manageable quantity while maximizing structural diversity. Structural diversity is achieved by pruning non-representative shapelets via submodular optimization. This increases the statistical power and utility of S5M compared to state-of-the-art approaches on simulated and real-world datasets. For patients admitted to the intensive care unit (ICU) showing signs of severe organ failure, we find temporal patterns in the sequential organ failure assessment score that are associated with in-ICU mortality. AVAILABILITY AND IMPLEMENTATION: S5M is an option in the python package of S3M: github.com/BorgwardtLab/S3M.

The results of clustering are often affected by covariates that are independent of the clusters one would like to discover. Traditionally, alternative clustering algorithms can be used to solve such clustering problems. However, these suffer from at least one of the following problems: (1) Continuous covariates or nonlinearly separable clusters cannot be handled; (2) assumptions are made about the distribution of the data; (3) one or more hyper-parameters need to be set. The presence of covariates also has an effect in a different type of problem such as semi-supervised learning. To the best of our knowledge, there is no existing method addressing the semi-supervised learning setting in the presence of covariates. Here we propose two novel algorithms, named kernel conditional clustering (KCC) and kernel conditional semi-supervised learning (KCSSL), whose objectives are derived from a kernel-based conditional dependence measure. KCC is parameter-light and makes no assumptions about the cluster structure, the covariates, or the distribution of the data, while KCSSL is fully parameter-free. On both simulated and real-world datasets, the proposed KCC and KCSSL algorithms perform better than state-of-the-art methods. The former detects the ground truth cluster structures more accurately, and the latter makes more accurate predictions.

Kernel methods are a powerful approach for learning on structured data. However, as we show in this paper, simple but common instances of the popular R-convolution kernel framework can be meaningless when assessing the similarity of two time series through their subsequences. We therefore propose a meaningful approach based on optimal transport theory that simultaneously captures local and global characteristics of time series. Moreover, we demonstrate that our method achieves competitive classification accuracy in comparison to state-of-the art methods across a wide variety of data sets.

Motivation: Most modern intensive care units record the physiological and vital signs of patients. These data can be used to extract signatures, commonly known as biomarkers, that help physicians understand the biological complexity of many syndromes. However, most biological biomarkers suffer from either poor predictive performance or weak explanatory power. Recent developments in time series classification focus on discovering shapelets, i.e. subsequences that are most predictive in terms of class membership. Shapelets have the advantage of combining a high predictive performance with an interpretable component-their shape. Currently, most shapelet discovery methods do not rely on statistical tests to verify the significance of individual shapelets. Therefore, identifying associations between the shapelets of physiological biomarkers and patients that exhibit certain phenotypes of interest enables the discovery and subsequent ranking of physiological signatures that are interpretable, statistically validated and accurate predictors of clinical endpoints. Results: We present a novel and scalable method for scanning time series and identifying discriminative patterns that are statistically significant. The significance of a shapelet is evaluated while considering the problem of multiple hypothesis testing and mitigating it by efficiently pruning untestable shapelet candidates with Tarone's method. We demonstrate the utility of our method by discovering patterns in three of a patient's vital signs: heart rate, respiratory rate and systolic blood pressure that are indicators of the severity of a future sepsis event, i.e. an inflammatory response to an infective agent that can lead to organ failure and death, if not treated in time. Availability and implementation: We make our method and the scripts that are required to reproduce the experiments publicly available at https://github.com/BorgwardtLab/S3M. Supplementary information: Supplementary data are available at Bioinformatics online.

Clustering results are often affected by covariates that are independent of the clusters one would like to discover. Traditionally, Alternative Clustering algorithms can be used to solve such a problem. However, these suffer from at least one of the following problems: i) continuous covariates or non-linearly separable clusters cannot be handled; ii) assumptions are made about the distribution of the data; iii) one or more hyper-parameters need to be set. Here we propose a novel algorithm, named Kernel Conditional Clustering (KCC), whose objective is derived from a kernel based conditional dependence measure. KCC is parameter-light and makes no assumptions about the cluster structure, the covariates, or the distribution of the data. On both simulated and real-world datasets, the proposed KCC algorithm detects the ground truth cluster structures more accurately than state-of-the-art alternative clustering methods.