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Manure management on dairy farms impacts how farmers maximize its value as fertilizer, reduce operating costs, and minimize environmental pollution potential. A persistent challenge on many farms is minimizing ammonia losses through volatilization during storage to maintain manure nitrogen content. Knowing the quantities of emitted pollutants is at the core of designing and improving mitigation strategies for livestock operations. Although process-based models have improved the accuracy of estimating ammonia emissions, complex systems such as manure storage still need to be solved because some underlying science still needs work. This study presents a novel physics-informed long short-term memory (PI-LSTM) modeling approach combining traditional process-based with recurrent neural networks to estimate ammonia loss from dairy manure during storage. The method entails inverse modeling to optimize hyperparameters to improve the accuracy of estimating physicochemical properties pertinent to ammonia's transport and surface emissions. The study used open data sets from two on-farm studies on liquid dairy manure storage in Switzerland and Indiana, U.S.A. The root mean square errors were 1.51 g m-2 h-1 for the PI-LSTM model, 3.01 g m-2 h-1 for the base compartmental process-based (Base-CPBM) model, and 2.17 g m-2 h-1 for the hyperparameter-tuned compartmental process-based (HT-CPBM) model. In addition, the PI-LSTM model outperformed the Base-CPBM and the HT-CPBM models by 20 to 80 % during summer and spring, when most annual ammonia emissions occur. The study demonstrated that incorporating physical knowledge into machine learning models improves generalization accuracy. The outcomes of this study provide the scientific basis to improve policymaking decisions and the design of suitable on-farm strategies to minimize manure nutrient losses on dairy farms during storage periods.

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Inference on unknown quantities in dynamical systems via observational data is essential for providing meaningful insight, furnishing accurate predictions, enabling robust control, and establishing appropriate designs for future experiments. Merging mathematical theory with empirical measurements in a statistically coherent way is critical and challenges abound, e.g., ill-posedness of the parameter estimation problem, proper regularization and incorporation of prior knowledge, and computational limitations. To address these issues, we propose a new method for learning parameterized dynamical systems from data. We first customize and fit a surrogate stochastic process directly to observational data, front-loading with statistical learning to respect prior knowledge (e.g., smoothness), cope with challenging data features like heteroskedasticity, heavy tails, and censoring. Then, samples of the stochastic process are used as "surrogate data" and point estimates are computed via ordinary point estimation methods in a modular fashion. Attractive features of this two-step approach include modularity and trivial parallelizability. We demonstrate its advantages on a predator-prey simulation study and on a real-world application involving within-host influenza virus infection data paired with a viral kinetic model, with comparisons to a more conventional Markov chain Monte Carlo (MCMC) based Bayesian approach.

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Gut microbiota and the immune system interact to maintain tissue homeostasis, but whether this interaction is involved in the pathogenesis of systemic lupus erythematosus (SLE) is unclear. Here we report that oral antibiotics given during active disease removed harmful bacteria from the gut microbiota and attenuated SLE-like disease in lupus-prone mice. Using MRL/lpr mice, we showed that antibiotics given after disease onset ameliorated systemic autoimmunity and kidney histopathology. They decreased IL-17-producing cells and increased the level of circulating IL-10. In addition, antibiotics removed Lachnospiraceae and increased the relative abundance of Lactobacillus spp., two groups of bacteria previously shown to be associated with deteriorated or improved symptoms in MRL/lpr mice, respectively. Moreover, we showed that the attenuated disease phenotype could be recapitulated with a single antibiotic vancomycin, which reshaped the gut microbiota and changed microbial functional pathways in a time-dependent manner. Furthermore, vancomycin treatment increased the barrier function of the intestinal epithelium, thus preventing the translocation of lipopolysaccharide, a cell wall component of Gram-negative Proteobacteria and known inducer of lupus in mice, into the circulation. These results suggest that mixed antibiotics or a single antibiotic vancomycin ameliorate SLE-like disease in MRL/lpr mice by changing the composition of gut microbiota.

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The compositions of in-host microbial communities (microbiota) play a significant role in host health, and a better understanding of the microbiota's role in a host's transition from health to disease or vice versa could lead to novel medical treatments. One of the first steps toward this understanding is modeling interaction dynamics of the microbiota, which can be exceedingly challenging given the complexity of the dynamics and difficulties in collecting sufficient data. Methods such as principal differential analysis, dynamic flux estimation, and others have been developed to overcome these challenges. Despite their advantages, these methods are still vastly underutilized in fields such as mathematical biology, and one potential reason for this is their sophisticated implementation. While this paper focuses on applying principal differential analysis to microbiota data, we also provide comprehensive details regarding the derivation and numerics of this method and include a functional implementation for readers' benefit. For further validation of these methods, we demonstrate the feasibility of principal differential analysis using simulation studies and then apply the method to intestinal and vaginal microbiota data. In working with these data, we capture experimentally confirmed dynamics while also revealing potential new insights into the system dynamics.

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Data from human clinical trials have shown that the hepatitis B virus (HBV) follows complex profiles, such as bi-phasic, tri-phasic, stepwise decay and rebound. We utilized a deterministic model of HBV kinetics following antiviral therapy to uncover the mechanistic interactions behind HBV dynamics. Analytical investigation of the model was used to separate the parameter space describing virus decay and rebound. Monte Carlo sampling of the parameter space was used to determine the virological, pharmacological and immunological factors that separate the bi-phasic and tri-phasic virus profiles. We found that the level of liver infection at the start of therapy best separates the decay patterns. Moreover, drug efficacy, ratio between division of uninfected and infected cells, and the strength of cytotoxic immune response are important in assessing the amount of liver damage experienced over time and in quantifying the duration of therapy leading to virus resolution in each of the observed profiles.

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Our work is motivated by a prostate cancer study aimed at identifying mRNA and miRNA biomarkers that are predictive of cancer recurrence after prostatectomy. It has been shown in the literature that incorporating known biological information on pathway memberships and interactions among biomarkers improves feature selection of high-dimensional biomarkers in relation to disease risk. Biological information is often represented by graphs or networks, in which biomarkers are represented by nodes and interactions among them are represented by edges; however, biological information is often not fully known. For example, the role of microRNAs (miRNAs) in regulating gene expression is not fully understood and the miRNA regulatory network is not fully established, in which case new strategies are needed for feature selection. To this end, we treat unknown biological information as missing data (i.e., missing edges in graphs), different from commonly encountered missing data problems where variable values are missing. We propose a new concept of imputing unknown biological information based on observed data and define the imputed information as the novel biological information. In addition, we propose a hierarchical group penalty to encourage sparsity and feature selection at both the pathway level and the within-pathway level, which, combined with the imputation step, allows for incorporation of known and novel biological information. While it is applicable to general regression settings, we develop and investigate the proposed approach in the context of semiparametric accelerated failure time models motivated by our data example. Data application and simulation studies show that incorporation of novel biological information improves performance in risk prediction and feature selection and the proposed penalty outperforms the extensions of several existing penalties.

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The analysis of survival endpoints subject to right-censoring is an important research area in statistics, particularly among econometricians and biostatisticians. The two most popular semiparametric models are the proportional hazards model and the accelerated failure time (AFT) model. Rank-based estimation in the AFT model is computationally challenging due to optimization of a non-smooth loss function. Previous work has shown that rank-based estimators may be written as solutions to linear programming (LP) problems. However, the size of the LP problem is O(n2 + p) subject to n2 linear constraints, where n denotes sample size and p denotes the dimension of parameters. As n and/or p increases, the feasibility of such solution in practice becomes questionable. Among data mining and statistical learning enthusiasts, there is interest in extending ordinary regression coefficient estimators for low-dimensions into high-dimensional data mining tools through regularization. Applying this recipe to rank-based coefficient estimators leads to formidable optimization problems which may be avoided through smooth approximations to non-smooth functions. We review smooth approximations and quasi-Newton methods for rank-based estimation in AFT models. The computational cost of our method is substantially smaller than the corresponding LP problem and can be applied to small- or large-scale problems similarly. The algorithm described here allows one to couple rank-based estimation for censored data with virtually any regularization and is exemplified through four case studies.

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BACKGROUND: Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. METHODS: First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. RESULTS: Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. CONCLUSIONS: The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported.

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Deregulations in the human energy metabolism may cause diseases such as obesity and type 2 diabetes mellitus. The origins of these pathologies are fairly unknown. The key role of the brain is the regulation of the complex whole body energy metabolism. The Selfish Brain Theory identifies the priority of brain energy supply in the competition for available energy resources within the organism. Here, we review mathematical models of the human energy metabolism supporting central aspects of the Selfish Brain Theory. First, we present a dynamical system modeling the whole body energy metabolism. This model takes into account the two central control mechanisms of the brain, i.e., allocation and appetite. Moreover, we present mathematical models of regulatory subsystems. We examine a neuronal model which specifies potential elements of the brain to sense and regulate cerebral energy content. We investigate a model of the HPA system regulating the allocation of energy within the organism. Finally, we present a robust modeling approach of appetite regulation. All models account for a systemic understanding of the human energy metabolism and thus do shed light onto defects causing metabolic diseases.

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In biomedical studies, it is of substantial interest to develop risk prediction scores using high-dimensional data such as gene expression data for clinical endpoints that are subject to censoring. In the presence of well-established clinical risk factors, investigators often prefer a procedure that also adjusts for these clinical variables. While accelerated failure time (AFT) models are a useful tool for the analysis of censored outcome data, it assumes that covariate effects on the logarithm of time-to-event are linear, which is often unrealistic in practice. We propose to build risk prediction scores through regularized rank estimation in partly linear AFT models, where high-dimensional data such as gene expression data are modeled linearly and important clinical variables are modeled nonlinearly using penalized regression splines. We show through simulation studies that our model has better operating characteristics compared to several existing models. In particular, we show that there is a non-negligible effect on prediction as well as feature selection when nonlinear clinical effects are misspecified as linear. This work is motivated by a recent prostate cancer study, where investigators collected gene expression data along with established prognostic clinical variables and the primary endpoint is time to prostate cancer recurrence. We analyzed the prostate cancer data and evaluated prediction performance of several models based on the extended c statistic for censored data, showing that 1) the relationship between the clinical variable, prostate specific antigen, and the prostate cancer recurrence is likely nonlinear, i.e., the time to recurrence decreases as PSA increases and it starts to level off when PSA becomes greater than 11; 2) correct specification of this nonlinear effect improves performance in prediction and feature selection; and 3) addition of gene expression data does not seem to further improve the performance of the resultant risk prediction scores.

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Dimension reduction, model and variable selection are ubiquitous concepts in modern statistical science and deriving new methods beyond the scope of current methodology is noteworthy. This article briefly reviews existing regularization methods for penalized least squares and likelihood for survival data and their extension to a certain class of penalized estimating function. We show that if one's goal is to estimate the entire regularized coefficient path using the observed survival data, then all current strategies fail for the Buckley-James estimating function. We propose a novel two-stage method to estimate and restore the entire Dantzig-regularized coefficient path for censored outcomes in a least-squares framework. We apply our methods to a microarray study of lung andenocarcinoma with sample size n = 200 and p = 1036 gene predictors and find 10 genes that are consistently selected across different criteria and an additional 14 genes that merit further investigation. In simulation studies, we found that the proposed path restoration and variable selection technique has the potential to perform as well as existing methods that begin with a proper convex loss function at the outset.

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The regulation of the energy metabolism is crucial to ensure the functionality of the entire organism. Deregulations may lead to severe pathologies such as obesity and type 2 diabetes mellitus. The decisive role of the brain as the active controller and heavy consumer in the complex whole body energy metabolism is the matter of recent research. Latest studies suggest that the brain's energy supply has the highest priority while all organs in the organism compete for the available energy resources. In our novel mathematical model, we address these new findings. We integrate energy fluxes and their control signals such as glucose fluxes, insulin signals as well as the ingestion momentum in our new dynamical system. As a novel characteristic, the hormone insulin is regarded as central feedback signal of the brain. Hereby, our model particularly contains the competition for energy between brain and body periphery. The analytical investigation of the presented dynamical system shows a stable long-term behavior of the entire energy metabolism while short time observations demonstrate the typical oscillating blood glucose variations as a consequence of food intake. Our simulation results demonstrate a realistic behavior even in situations like exercise or exhaustion, and key elements like the brain's preeminence are reflected. The presented dynamical system is a step towards a systemic understanding of the human energy metabolism and thus may shed light to defects causing diseases based on deregulations in the energy metabolism.

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