On the origins and rarity of locally but not globally identifiable parameters in biological modeling

Structural identifiability determines the possibility of estimating the parameters of a model by observing its output in an ideal experiment. If a parameter is structurally locally identifiable, but not globally (SLING), its true value cannot be uniquely inferred because several equivalent solutions exist. In biological modeling it is sometimes assumed that local identifiability entails global identifiability, which is convenient because local identifiability tests are typically less computationally demanding than global tests. However, this assumption has never been investigated beyond demonstrating the existence of counter-examples. To clarify this matter, in this paper we began by asking how often a structurally locally identifiable parameter is not globally identifiable in systems biology. To answer this question empirically we assembled a collection of 102 mathematical models from the literature, with a total of 763 parameters. We analysed their identifiability, determining that approximately 5% of the parameters are SLING. Next we investigated how the SLING parameters arise, tracing their origin to particular features of the model equations. Finally, we investigated the possibility of obtaining false estimates. Some of the solutions that are mathematically equivalent to the true one involved parameters and/or initial conditions with negative values, which are not biologically meaningful. In other cases the true solution and the equivalent one were in the same range. These results provide insight about a previously unexplored hypothesis, and suggest that in most (albeit not all) systems biology applications it suffices to test for structural local identifiability.MCIN/AEI/ 10.13039/50110001103300004837 | Ref. PID2020-113992RA-I00MCIN/AEI/ 10.13039/50110001103300004837 | Ref. RYC-2019-027537-IXunta de Galicia | Ref. ED431F 2021/00

Benchmarking tools for a priori identifiability analysis

Motivation: The theoretical possibility of determining the state and parameters of a dynamic model by measuring its outputs is given by its structural identifiability and observability. These properties should be analysed before attempting to calibrate a model, but their a priori analysis can be challenging, requiring symbolic calculations that often have a high computational cost. In recent years a number of software tools have been developed for this task, mostly in the systems biology community. These tools have vastly different features and capabilities, and a critical assessment of their performance is still lacking. Results: Here we present a comprehensive study of the computational resources available for analysing structural identifiability. We consider 13 software tools developed in 7 programming languages and evaluate their performance using a set of 25 case studies created from 21 models. Our results reveal their strengths and weaknesses, provide guidelines for choosing the most appropriate tool for a given problem, and highlight opportunities for future developments. Availability: https://github.com/Xabo-RB/Benchmarking_files.Xunta de Galicia | Ref. ED431F 2021/003Agencia Estatal de Investigación | Ref. PID2020-113992RA-I00MCIN/AEI/10.13039/501100011033 | Ref. RYC-2019-027537-IFinanciado para publicación en acceso aberto: Universidade de Vigo/CISU

STRIKE-GOLDD 4.0: user-friendly, efficient analysis of structural identifiability and observability

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGMotivation: STRIKE-GOLDD is a toolbox that analyses the structural identifiability and observability of possibly non-linear, non-rational ODE models that may have known and unknown inputs. Its broad applicability comes at the expense of a lower computational efficiency than other tools. Results: STRIKE-GOLDD 4.0 includes a new algorithm, ProbObsTest, specifically designed for the analysis of rational models. ProbObsTest is significantly faster than the previously available FISPO algorithm when applied to computationally expensive models. Providing both algorithms in the same toolbox allows combining generality and computational efficiency. STRIKE-GOLDD 4.0 is implemented as a Matlab toolbox with a user-friendly graphical interface. Availability and implementation: STRIKE-GOLDD 4.0 is a free and open-source tool available under a GPLv3 license. It can be downloaded from GitHub at https://github.com/afvillaverde/strike-goldd. Supplementary information: Supplementary data are available at Bioinformatics online.MCIN/AEI/10.13039/501100011033 | Ref. PID2020-113992RA-I00MCIN/AEI/10.13039/501100011033 | Ref. RYC-2019-027537-IXunta de Galicia | Ref. ED431F 2021/00

STRIKE-GOLDD 4.0: user-friendly, efficient analysis of structural identifiability and observability

Structural identifiability and observability are desirable properties of systems biology models. Many software toolboxes have been developed for their analysis in the last decades. STRIKE-GOLDD is a generally applicable tool that can analyse non-linear, non-rational ODE models with unknown inputs. However, this generality comes at the expense of a lower computational efficiency than other tools. Here we present STRIKE-GOLDD 4.0, which includes a new algorithm, ProbObsTest, specifically designed for the analysis of rational models. ProbObsTest is significantly faster than the FISPO algorithm - which was already available in older versions of the toolbox - when applied to computationally expensive models. An important feature of both algorithms is their ability to analyse models with unknown inputs. Thus, their coexistence in the same toolbox provides a combination of general applicability and computational efficiency. STRIKE-GOLDD 4.0 is implemented as a free and open-source Matlab toolbox with a user-friendly graphical interface. It is available under a GPLv3 license and it can be downloaded from GitHub at https://github.com/afvillaverde/strike-goldd.Comment: 14 pages, 1 figur

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Emergency medical services utilisation among febrile children attending emergency departments across Europe: an observational multicentre study

Abstract Children constitute 6–10% of all patients attending the emergency department (ED) by emergency medical services (EMS). However, discordant EMS use in children occurs in 37–61% with fever as an important risk factor. We aimed to describe EMS utilisation among febrile children attending European EDs. This study is part of an observational multicentre study assessing management and outcome in febrile children up to 18 years (MOFICHE) attending twelve EDs in eight European countries. Discordant EMS use was defined as the absence of markers of urgency including intermediate/high triage urgency, advanced diagnostics, treatment, and admission in children transferred by EMS. Multivariable logistic regression analyses were performed for the association between (1) EMS use and markers of urgency, and (2) patient characteristics and discordant EMS use after adjusting all analyses for the covariates age, gender, visiting hours, presenting symptoms, and ED setting. A total of 5464 (15%, range 0.1–42%) children attended the ED by EMS. Markers of urgency were more frequently present in the EMS group compared with the non-EMS group. Discordant EMS use occurred in 1601 children (29%, range 1–59%). Age and gender were not associated with discordant EMS use, whereas neurological symptoms were associated with less discordant EMS use (aOR 0.2, 95%CI 0.1–0.2), and attendance out of office hours was associated with more discordant EMS use (aOR 1.6, 95%CI 1.4–1.9). Settings with higher percentage of self-referrals to the ED had more discordant EMS use (p &lt; 0.05).  Conclusion: There is large practice variation in EMS use in febrile children attending European EDs. Markers of urgency were more frequently present in children in the EMS group. However, discordant EMS use occurred in 29%. Further research is needed on non-medical factors influencing discordant EMS use in febrile children across Europe, so that pre-emptive strategies can be implemented. What is Known: •Children constitute around 6–10% of all patients attending the emergency department by emergency medical services. •Discordant EMS use occurs in 37–61% of all children, with fever as most common presenting symptom for discordant EMS use in children. What is New: •There is large practice variation in EMS use among febrile children across Europe with discordance EMS use occurring in 29% (range 1–59%), which was associated with attendance during out of office hours and with settings with higher percentage of self-referrals to the ED. •Future research is needed focusing on non-medical factors (socioeconomic status, parental preferences and past experience, healthcare systems, referral pathways, out of hours services provision) that influence discordant EMS use in febrile children across Europe. </jats:p