Likelihood based observability analysis and confidence intervals for predictions of dynamic models

Mechanistic dynamic models of biochemical networks such as Ordinary Differential Equations (ODEs) contain unknown parameters like the reaction rate constants and the initial concentrations of the compounds. The large number of parameters as well as their nonlinear impact on the model responses hamper the determination of confidence regions for parameter estimates. At the same time, classical approaches translating the uncertainty of the parameters into confidence intervals for model predictions are hardly feasible. In this article it is shown that a so-called prediction profile likelihood yields reliable confidence intervals for model predictions, despite arbitrarily complex and high-dimensional shapes of the confidence regions for the estimated parameters. Prediction confidence intervals of the dynamic states allow a data-based observability analysis. The approach renders the issue of sampling a high-dimensional parameter space into evaluating one-dimensional prediction spaces. The method is also applicable if there are non-identifiable parameters yielding to some insufficiently specified model predictions that can be interpreted as non-observability. Moreover, a validation profile likelihood is introduced that should be applied when noisy validation experiments are to be interpreted. The properties and applicability of the prediction and validation profile likelihood approaches are demonstrated by two examples, a small and instructive ODE model describing two consecutive reactions, and a realistic ODE model for the MAP kinase signal transduction pathway. The presented general approach constitutes a concept for observability analysis and for generating reliable confidence intervals of model predictions, not only, but especially suitable for mathematical models of biological systems

Constructing Exact Confidence Regions on Parameter Manifolds of Non-Linear Models

Using the mathematical framework of information geometry, we introduce a novel method which allows one to efficiently determine the exact shape of simultaneous confidence regions for non-linearly parametrised models. Furthermore, we show how pointwise confidence bands around the model predictions can be constructed from detailed knowledge of the exact confidence region with little additional computational effort. We exemplify our methods using inference problems in cosmology and epidemic modelling. An open source implementation of the developed schemes is publicly available via the InformationGeometry.jl package for the Julia programming language.Comment: 24 page

Prevalence of and risk factors for prostatitis in African American men: The Flint Men's Health Study

INTRODUCTION Prostatitis is a common, yet ill-defined condition without clear diagnostic criteria and treatment strategies. Previous studies examining the prevalence and correlates of prostatitis are limited in their inclusion of primarily white populations. The objective of the current study was to identify prevalence of and risk factors for prostatitis in a population-based sample of African-American men. METHODS In 1996, a probability sample of 703 African-American men, aged 40–79, residing in Genesee County, Michigan without a prior history of prostate cancer/surgery provided responses to a structured interview-administered questionnaire which elicited information regarding sociodemographics, current stress and health ratings, and past medical history, including history of physician diagnosed prostatitis, BPH and sexually transmitted diseases. Logistic regression was used to identify predictors of prostatitis after adjustment for age. RESULTS Forty-seven (6.7%) of the 703 men reported a history of prostatitis. Increased frequency of sexual activity and physical activity were significantly associated with decreased odds of disease. Moderate to severe lower urinary tract symptoms (LUTS) and a history of BPH were significantly associated with prostatitis after adjustment for age. CONCLUSION After adjustment for age, LUTS severity and history of BPH were associated with increased odds of prostatitis. BMI, physical activity and sexual frequency were associated with decreased odds of prostatitis. Finally, poor emotional and physical health, high perceived stress and low social support were associated with an increased risk of prostatitis history. Importantly, these findings suggest that the primary risk factors for this condition are largely modifiable and highlight potential targets for future prevention. Prostate 69: 24–32, 2009. © 2008 Wiley–Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61311/1/20846_ftp.pd

Benchmarking of analysis strategies for data-independent acquisition proteomics using a large-scale dataset comprising inter-patient heterogeneity

Numerous software tools exist for data-independent acquisition (DIA) analysis of clinical samples, necessitating their comprehensive benchmarking. We present a benchmark dataset comprising real-world inter-patient heterogeneity, which we use for in-depth benchmarking of DIA data analysis workflows for clinical settings. Combining spectral libraries, DIA software, sparsity reduction, normalization, and statistical tests results in 1428 distinct data analysis workflows, which we evaluate based on their ability to correctly identify differentially abundant proteins. From our dataset, we derive bootstrap datasets of varying sample sizes and use the whole range of bootstrap datasets to robustly evaluate each workflow. We find that all DIA software suites benefit from using a gas-phase fractionated spectral library, irrespective of the library refinement used. Gas-phase fractionation-based libraries perform best against two out of three reference protein lists. Among all investigated statistical tests non-parametric permutation-based statistical tests consistently perform best

Benchmarking of analysis strategies for data-independent acquisition proteomics using a large-scale dataset comprising inter-patient heterogeneity

Numerous software tools exist for data-independent acquisition (DIA) analysis of clinical samples, necessitating their comprehensive benchmarking. We present a benchmark dataset comprising real-world inter-patient heterogeneity, which we use for in-depth benchmarking of DIA data analysis workflows for clinical settings. Combining spectral libraries, DIA software, sparsity reduction, normalization, and statistical tests results in 1428 distinct data analysis workflows, which we evaluate based on their ability to correctly identify differentially abundant proteins. From our dataset, we derive bootstrap datasets of varying sample sizes and use the whole range of bootstrap datasets to robustly evaluate each workflow. We find that all DIA software suites benefit from using a gas-phase fractionated spectral library, irrespective of the library refinement used. Gas-phase fractionation-based libraries perform best against two out of three reference protein lists. Among all investigated statistical tests non-parametric permutation-based statistical tests consistently perform best

Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range

Quantitative analysis of time-resolved data in primary erythroid progenitor cells reveals that a dual negative transcriptional feedback mechanism underlies the ability of STAT5 to respond to the broad spectrum of physiologically relevant Epo concentrations

Data-driven prediction of COVID-19 cases in Germany for decision making

The COVID-19 pandemic has led to a high interest in mathematical models describing and predicting the diverse aspects and implications of the virus outbreak. Model results represent an important part of the information base for the decision process on different administrative levels. The Robert-Koch-Institute (RKI) initiated a project whose main goal is to predict COVID-19-specific occupation of beds in intensive care units: Steuerungs-Prognose von Intensivmedizinischen COVID-19 Kapazitäten (SPoCK). The incidence of COVID-19 cases is a crucial predictor for this occupation

Prognosemodelle zur Steuerung von intensivmedizinischen COVID-19-Kapazitäten in Deutschland

Hintergrund: Zeitdynamische Prognosemodelle spielen eine zentrale Rolle zur Steuerung von intensivmedizinischen COVID-19-Kapazitäten im Pandemiegeschehen. Ein wichtiger Vorhersagewert (Prädiktor) für die zukünftige intensivmedizinische (ITS-)COVID-19-Bettenbelegungen ist die Anzahl der SARS-CoV-2-Neuinfektionen in der Bevölkerung, die wiederum stark von Schwankungen im Wochenverlauf, Meldeverzug, regionalen Unterschieden, Dunkelziffer, zeitabhängiger Ansteckungsrate, Impfungen, SARS-CoV-2-Virusvarianten sowie von nichtpharmazeutischen Eindämmungsmaßnahmen abhängt. Darüber hinaus wird die aktuelle und auch zukünftige COVID-ITS-Belegung maßgeblich von den intensivmedizinischen Entlassungs- und Sterberaten beeinflusst. Methode: Sowohl die Anzahl der SARS-CoV-2-Neuinfektionen in der Bevölkerung als auch die intensivmedizinischen COVID-19-Bettenbelegungen werden bundesweit flächendeckend erfasst. Diese Daten werden tagesaktuell mit epidemischen SEIR-Modellen aus gewöhnlichen Differenzialgleichungen und multiplen Regressionsmodellen statistisch analysiert. Ergebnisse: Die Prognoseergebnisse der unmittelbaren Entwicklung (20-Tage-Vorhersage) der ITS-Belegung durch COVID-19-Patienten*innen werden Entscheidungsträgern auf verschiedenen überregionalen Ebenen zur Verfügung gestellt. Schlussfolgerung: Die Prognosen werden der Entwicklung von betreibbaren intensivmedizinischen Bettenkapazitäten gegenübergestellt, um frühzeitig Kapazitätsengpässe zu erkennen und kurzfristig reaktive Handlungssteuerungen, wie etwa überregionale Verlegungen, zu ermöglichen.Background: Time-series forecasting models play a central role in guiding intensive care coronavirus disease 2019 (COVID-19) bed capacity in a pandemic. A key predictor of future intensive care unit (ICU) COVID-19 bed occupancy is the number of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the general population, which in turn is highly associated with week-to-week variability, reporting delays, regional differences, number of unknown cases, time-dependent infection rates, vaccinations, SARS-CoV‑2 virus variants, and nonpharmaceutical containment measures. Furthermore, current and also future COVID ICU occupancy is significantly influenced by ICU discharge and mortality rates. Methods: Both the number of new SARS-CoV‑2 infections in the general population and intensive care COVID-19 bed occupancy rates are recorded in Germany. These data are statistically analyzed on a daily basis using epidemic SEIR (susceptible, exposed, infection, recovered) models using ordinary differential equations and multiple regression models. Results: Forecast results of the immediate trend (20-day forecast) of ICU occupancy by COVID-19 patients are made available to decision makers at various levels throughout the country. Conclusion: The forecasts are compared with the development of available ICU bed capacities in order to identify capacity limitations at an early stage and to enable short-term solutions to be made, such as supraregional transfers.Peer Reviewe