Key Points• Acquired pathogenic mutations in SAMHD1 are found in up to 11% of relapsed/refractory patients with CLL. • SAMHD1 is mobilized to sites of DNA damage.SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germ-line SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency and reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development. (Blood. 2014;123(7):1021-1031)

Quantitative systems pharmacology (QSP) models aim to describe mechanistically the pathophysiology of disease and predict the effects of therapies on that disease. For most drug development applications, it is important to predict not only the mean response to an intervention but also the distribution of responses, due to inter-patient variability. Given the necessary complexity of QSP models, and the sparsity of relevant human data, the parameters of QSP models are often not well determined. One approach to overcome these limitations is to develop alternative virtual patients (VPs) and virtual populations (Vpops), which allow for the exploration of parametric uncertainty and reproduce inter-patient variability in response to perturbation. Here we evaluated approaches to improve the efficiency of generating Vpops. We aimed to generate Vpops without sacrificing diversity of the VPs' pathophysiologies and phenotypes. To do this, we built upon a previously published approach (Allen et al., 2016) by (a) incorporating alternative optimization algorithms (genetic algorithm and Metropolis-Hastings) or alternatively (b) augmenting the optimized objective function. Each method improved the baseline algorithm by requiring significantly fewer plausible patients (precursors to VPs) to create a reasonable Vpop.

Weaning from mechanical ventilation in the intensive care unit (ICU) is a complex clinical problem and relevant for future organ engineering. Prolonged mechanical ventilation (MV) leads to a range of medical complications that increases length of stay and costs as well as contributes to morbidity and even mortality and long-term quality of life. The need to reduce MV is both clinical and economical. Artificial intelligence or machine learning (ML) methods are promising opportunities to positively influence patient outcomes. ML methods have been proposed to enhance clinical decisions processes by using the large amount of digital information generated in the ICU setting. There is a particular interest in empirical methods (such as ML) to improve management of "difficult-to-wean" patients, due to the associated costs and adverse events associated with this population. A systematic literature search was performed using the OVID, IEEEXplore, PubMed, and Web of Science databases. All publications that included (1) the application of ML to weaning from MV in the ICU and (2) a clinical outcome measurement were reviewed. A checklist to assess the study quality of medical ML publications was modified to suit the critical assessment of ML in MV weaning literature. The systematic search identified nine studies that used ML for weaning management from MV in critical care. The weaning management application areas included (1) prediction of successful spontaneous breathing trials (SBTs), (2) prediction of successful extubation, (3) prediction of arterial blood gases, and (4) ventilator setting and oxygenation-adjustment advisory systems. Seven of the nine studies scored seven out of eight on the quality index. The remaining two of the nine studies scored one out of eight on the quality index. This scoring may, in part, be explained by the publications' focus on technical novelty, and therefore focusing on issues most important to a technical audience, instead of issues most important for a systematic medical review. This review showed that only a limited number of studies have started to assess the efficacy and effectiveness of ML for MV in the ICU. However, ML has the potential to be applied to the prediction of SBT failure, extubation failure, and blood gases, and also the adjustment of ventilator and oxygenation settings. The available databases for the development of ML in this clinical area may still be inadequate. None of the reviewed studies reported on the procedure, treatment, or sedation strategy undergone by patients. Such information is unlikely to be required in a technical publication but is potentially vital to the development ML techniques that are sufficiently robust to meet the needs of the "difficult-to-wean" patient population.

Gaussian process regression (GPR) provides a means to generate flexible personalized models of time series of patient vital signs. These models can perform useful clinical inference in ways that population-based models cannot. A challenge for the use of personalized models is that they must be amenable to a wide range of parameterizations, to accommodate the plausible physiology of any patient in the population. Additionally, optimal performance is typically achieved when models are regularized in light of the knowledge of the physiology of the individual patient. In this paper, we describe a method to build GP models with varying complexity (via covariance kernels) and regularization (via fixed priors over hyperparameters) on a patient-specific level, for the purpose of robust vital-sign forecasting. To this end, our results present evidence in support of two main hypotheses: 1) the use of patient-specific models can outperform population-based models for useful clinical tasks, such as vital-sign forecasting; and 2) the optimal values of (hyper)parameters of these models are best determined by sophisticated methods of optimization, due to high correlation between dimensions of the search space. The resulting models are sufficiently robust to inform clinicians of a patient's vital-sign trajectory and warn of imminent deterioration.

The step-down unit (SDU) is a high-acuity hospital environment, to which patients may be sent after discharge from the intensive care unit (ICU). About 1- in-7 patients will deteriorate in the SDU and require emergency readmission to the ICU. Upon readmission, these patients experience significantly higher mortality risks and lengths of stay. Gaussian process regression (GPR) models are proposed as a flexible, principled, probabilistic method to address the clinical need to monitor continuously patient time-series of vital signs acquired in the SDU. The proposed GPR models focus on the robust forecasting of patient heart rate time-series and on the early detection of patient deterioration. The proposed methods are tested with an SDU data set from the University of Pittsburgh Medical Center, comprising 333 patients, 59 of whom had at least one verified clinical emergency event. Results suggest that GPR-based heart rate monitoring provides superior advanced warning of deterioration compared to the current clinical practice of rules-based thresholding, and slightly outperforms the current state-of-the-art kernel density method, which requires 4 additional vital sign features.

22Quantitative systems pharmacology (QSP) models aim to describe mechanistically 23 the pathophysiology of disease and predict the effects of therapies on that disease. 24For most drug development applications, it is important to predict not only the 25 mean response to an intervention but also the distribution of responses, due to 26 inter-patient variability. Given the necessary complexity of QSP models, and the 27 sparsity of relevant human data, the parameters of QSP models are often not well 28 determined. . CC-BY-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

The management of patient well-being can be performed by monitoring continuous time-series vital-sign data via low-cost wearable devices. Automated algorithms may then be used with the resulting data to provide early warning of deterioration of the health of an individual. Such algorithms are typically trained for a large population without considering the time-variability and inter-subject variability of the data being collected. In the case where limited numbers of subjects are available, it is difficult to create a generalized population model from a small sample size. Furthermore, some ''normal'' patients may exhibit different physiological patterns when compared to other ''normal'' patients, forming multiple ''normal'' clusters/subgroups. This also makes inferring a population model difficult. It is, therefore, preferable to develop patient/subgroup-specific time-series models to overcome these challenges. We propose using Bayesian hierarchical Gaussian processes to infer the hidden latent structure of the vital sign's trajectory for each individual patient or group of patients who share similar patterns. We further demonstrate the feasibility of such a model in novelty detection, using the symmetric Kullback-Leibler divergence. This allows us to identify any patterns that correspond to ''normal'' or ''abnormal'' physiology, and further classifying ''abnormal'' patterns from a model of ''normal'' latent trajectories. We tested our approach using two real datasets for different monitoring scenarios. Our model was compared to the performance of the state-ofthe-art unsupervised clustering algorithms, demonstrating at least 10% improvement in accuracy. We further benchmarked against two one-class classifiers and showed at least 5% accuracy improvement when using the proposed metrics in identifying abnormal physiological episodes. INDEX TERMS Physiology, patient monitoring, pattern analysis, Bayes methods.

Health informatics systems based on machine learning are in their infancy and the translation of such systems into clinical management has yet to be performed at scale.