Specifications of standards in systems and synthetic biology: status and developments in 2022 and the COMBINE meeting 2022.

This special issue of the Journal of Integrative Bioinformatics contains updated specifications of COMBINE standards in systems and synthetic biology. The 2022 special issue presents three updates to the standards: CellML 2.0.1, SBML Level 3 Package: Spatial Processes, Version 1, Release 1, and Synthetic Biology Open Language (SBOL) Version 3.1.0. This document can also be used to identify the latest specifications for all COMBINE standards. In addition, this editorial provides a brief overview of the COMBINE 2022 meeting in Berlin.

Osteogenesis Imperfecta: Multidisciplinary and Goal-Centered Care.

We describe a case of osteogenesis imperfecta (OI) in a late preterm female of 35-week gestation. The mother did have a history of substance abuse, poor prenatal care, and hypertension. On the day of delivery, an ultrasound revealed skeletal dysplasia and breech with nonreassuring fetal tracing, leading to an emergency cesarean. The clinical exam was concerning for OI, and postnatal care was focused on optimizing respiratory status and minimizing pain and discomfort during routine care. Genetics, endocrine, orthopaedics, and palliative care were all involved to diagnose and educate the family. Support and education were needed for bedside staff to minimize angst at performing routine care, given the high risk of fractures. While initially stable on minimal oxygen, once the diagnosis of type III OI was made, a progressively deforming condition with respiratory status decompensation, the family wished to minimize suffering, limited aggressive medical care, and focused on comfort. The infant eventually died from respiratory failure in the neonatal intensive care unit. We present this case to demonstrate the need for an interdisciplinary team approach to support both family and staff in cases of OI.

Osteogenesis Imperfecta: Multidisciplinary and Goal-Centered Care.

We describe a case of osteogenesis imperfecta (OI) in a late preterm female of 35-week gestation. The mother did have a history of substance abuse, poor prenatal care, and hypertension. On the day of delivery, an ultrasound revealed skeletal dysplasia and breech with nonreassuring fetal tracing, leading to an emergency cesarean. The clinical exam was concerning for OI, and postnatal care was focused on optimizing respiratory status and minimizing pain and discomfort during routine care. Genetics, endocrine, orthopaedics, and palliative care were all involved to diagnose and educate the family. Support and education were needed for bedside staff to minimize angst at performing routine care, given the high risk of fractures. While initially stable on minimal oxygen, once the diagnosis of type III OI was made, a progressively deforming condition with respiratory status decompensation, the family wished to minimize suffering, limited aggressive medical care, and focused on comfort. The infant eventually died from respiratory failure in the neonatal intensive care unit. We present this case to demonstrate the need for an interdisciplinary team approach to support both family and staff in cases of OI.

Addressing barriers in comprehensiveness, accessibility, reusability, interoperability and reproducibility of computational models in systems biology.

Computational models are often employed in systems biology to study the dynamic behaviours of complex systems. With the rise in the number of computational models, finding ways to improve the reusability of these models and their ability to reproduce virtual experiments becomes critical. Correct and effective model annotation in community-supported and standardised formats is necessary for this improvement. Here, we present recent efforts toward a common framework for annotated, accessible, reproducible and interoperable computational models in biology, and discuss key challenges of the field.

Specifications of standards in systems and synthetic biology: status and developments in 2021.

This special issue of the Journal of Integrative Bioinformatics contains updated specifications of COMBINE standards in systems and synthetic biology. The 2021 special issue presents four updates of standards: Synthetic Biology Open Language Visual Version 2.3, Synthetic Biology Open Language Visual Version 3.0, Simulation Experiment Description Markup Language Level 1 Version 4, and OMEX Metadata specification Version 1.2. This document can also be consulted to identify the latest specifications of all COMBINE standards.

Navigating Medical Care for a Young Adult with Developmental Disability.

CASE: Sam is a 20-year-old young man with intermittent gastritis, autism spectrum disorder, and intellectual disability who was admitted to the hospital because of nutritional concerns. His parents have legal guardianship and report that he has had increasing frequency of refusal to eat, resulting in a 15-pound weight loss over the past 3 months. On admission, a multidisciplinary team including specialists in gastroenterology, nutrition, feeding (behavioral and mechanical), psychiatry, palliative care, and social work was engaged to develop an evaluation and care plan. Sam's nutritional assessment was significant for severe malnutrition. An upper endoscopy was performed and was without abnormalities, including signs of significant gastritis.An upper endoscopy was performed and was without abnormalities, including signs of significant gastritis.A carefully obtained history found that Sam does not have a primary care physician. He was recently hospitalized at another facility because of his weight loss and nutritional concerns but was discharged against medical advice because of parental dissatisfaction with his care. His mother shared that she has tried many strategies to encourage Sam to eat including pushing spoons of food into his mouth, syringe feeding, and verbally pleading with Sam to take a bite, but all of these have been without success.Because of concerns that persistent attempts to verbally and physically coerce Sam to eat may be contributing to his aversion to food/eating, the feeding team provided Sam's parents with education and coaching for utilization of behavioral cues to determine when Sam wanted to eat. Despite parents expressing their understanding of the importance of avoiding physical attempts to "make" Sam eat and the team palliative care physician meeting with Sam's parents to elicit their goals for Sam's care, his nurses reported observing several instances of Sam's mother tapping a loaded spoon on his lips. Because of minimal oral intake, a nasogastric tube was placed for provision of hydration and nutrition. Sam's parents consented to the use of soft restraints and the presence of a bedside patient care assistant because of Sam becoming agitated and pulling at the tube.After 10 days of hospitalization, Sam was taking about 50% of his goal intake by mouth. Unfortunately, Sam removed his NG tube, and his parents refused to allow the tube to be replaced. Sam's parents then discharged him against medical advice, stating that they believed he would recover better at home. What are important considerations in caring for patients like Sam in the hospital setting and beyond?

The Individualized Addictions Consultation Team Residential Program: A Creative Solution for Integrating Care for Veterans With Substance Use Disorders Too Complex for Other Residential Treatment Programs.

OBJECTIVES: The Veterans Affairs (VA) healthcare system is one of the main providers of substance use treatment within the United States, and many veterans with a substance use disorder (SUD) present with co-occurring diagnoses or other concerns. Though there has been increasing recognition of the need for integration of treatments for SUD and comorbid mental illness, there have been limited studies of such programs, particularly within the VA healthcare system. To address that gap in the literature, this paper examines treatment outcomes in an integrated model of dual diagnosis residential treatment for veterans: the Individualized Addictions Consultation Team (I-ACT) program. Methods: The current paper draws from clinical outcome evaluation data within a residential treatment program at a large Midwestern VA Medical Center (VAMC). The I-ACT program provides residential substance abuse treatment to individuals with a primary SUD and other factors that interfere with the successful completion of a traditional residential rehabilitation program. Between 2017 and 2018, 130 individuals (97.7% men, average age = 60.62 years) entered the I-ACT program. As part of standard measurement-based care, veterans were administered the Brief Addiction Monitor and the Patient Health Questionnaire-9 at admission and discharge. Results: Most individuals (74.6%) who entered I-ACT completed the residential program (average length of stay 34.2 days). Scores on both measures significantly decreased from intake to discharge (p < .001), with the change in depression scores indicating clinically significant improvement. Those with an additional mental health diagnosis achieved similar decreases in substance use symptoms and had lower depression scores at discharge than those with a SUD alone. Conclusions: Our results indicate that even for veterans who may not benefit from traditional SUD treatment programs, a more integrated and personalized residential program can be effective.

Diagnostic accuracy of fetal growth charts for placenta-related fetal growth restriction.

INTRODUCTION: The choice of fetal growth chart to be used in antenatal screening for fetal growth restriction (FGR) has an important impact on the proportion of fetuses diagnosed as small for gestational age (SGA), and on the detection rate for FGR. We aimed to compare diagnostic accuracy of SGA diagnosed using four different common fetal growth charts [Hadlock, Intergrowth-21st (IG21), World Health Organization (WHO), and National Institute of Child Health and Human Development (NICHD)], for abnormal placental pathology. METHODS: A secondary analysis of data from a prospective cohort study in low-risk nulliparous women. The exposure was SGA (birthweight <10th centile for gestational age) using each of the four charts. The outcomes were one of three types of abnormal placental pathology associated with fetal growth restriction: maternal vascular malperfusion (MVM), chronic villitis, and fetal vascular malperfusion. RESULTS: A total of 742 nulliparous women met the study criteria. The proportion of SGA was closest to the expected rate of 10% using the Hadlock chart (12.7%). The detection rates (DR) and false positive rates (FPR) for MVM pathology were similar for the Hadlock (DR = 53.1%, FPR = 10.8%), WHO (DR = 59.4%, FPR = 14.2%), and NICHD (DR = 53.1%, FPR = 12.3%) charts, and each was superior when compared to the IG21 chart (DR = 34.4%, FPR = 3.8%, p < 0.001). The diagnosis of SGA was associated with increased risks of preeclampsia and preterm birth for all four charts. DISCUSSION: The selection of fetal growth chart to be used in screening programs for FGR has important implications with regard to the false positive and detection rate for FGR.

cellmlmanip and chaste_codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians.

Hundreds of different mathematical models have been proposed for describing electrophysiology of various cell types. These models are quite complex (nonlinear systems of typically tens of ODEs and sometimes hundreds of parameters) and software packages such as the Cancer, Heart and Soft Tissue Environment (Chaste) C++ library have been designed to run simulations with these models in isolation or coupled to form a tissue simulation. The complexity of many of these models makes sharing and translating them to new simulation environments difficult. CellML is an XML format that offers a widely-adopted solution to this problem. This paper specifically describes the capabilities of two new Python tools: the cellmlmanip library for reading and manipulating CellML models; and chaste_codegen, a CellML to C++ converter. These tools provide a Python 3 replacement for a previous Python 2 tool (called PyCML) and they also provide additional new features that this paper describes. Most notably, they can generate analytic Jacobians without the use of proprietary software, and also find singularities occurring in equations and automatically generate and apply linear approximations to prevent numerical problems at these points.

Systems Biology Markup Language (SBML) Level 3 Package: Distributions, Version 1, Release 1.

Biological models often contain elements that have inexact numerical values, since they are based on values that are stochastic in nature or data that contains uncertainty. The Systems Biology Markup Language (SBML) Level 3 Core specification does not include an explicit mechanism to include inexact or stochastic values in a model, but it does provide a mechanism for SBML packages to extend the Core specification and add additional syntactic constructs. The SBML Distributions package for SBML Level 3 adds the necessary features to allow models to encode information about the distribution and uncertainty of values underlying a quantity.

SBML Level 3: an extensible format for the exchange and reuse of biological models.

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution.

Systems biology markup language (SBML) level 3 package: multistate, multicomponent and multicompartment species, version 1, release 2.

Rule-based modeling is an approach that permits constructing reaction networks based on the specification of rules for molecular interactions and transformations. These rules can encompass details such as the interacting sub-molecular domains and the states and binding status of the involved components. Conceptually, fine-grained spatial information such as locations can also be provided. Through "wildcards" representing component states, entire families of molecule complexes sharing certain properties can be specified as patterns. This can significantly simplify the definition of models involving species with multiple components, multiple states, and multiple compartments. The systems biology markup language (SBML) Level 3 Multi Package Version 1 extends the SBML Level 3 Version 1 core with the "type" concept in the Species and Compartment classes. Therefore, reaction rules may contain species that can be patterns and exist in multiple locations. Multiple software tools such as Simmune and BioNetGen support this standard that thus also becomes a medium for exchanging rule-based models. This document provides the specification for Release 2 of Version 1 of the SBML Level 3 Multi package. No design changes have been made to the description of models between Release 1 and Release 2; changes are restricted to the correction of errata and the addition of clarifications.

The first 10 years of the international coordination network for standards in systems and synthetic biology (COMBINE).

This paper presents a report on outcomes of the 10th Computational Modeling in Biology Network (COMBINE) meeting that was held in Heidelberg, Germany, in July of 2019. The annual event brings together researchers, biocurators and software engineers to present recent results and discuss future work in the area of standards for systems and synthetic biology. The COMBINE initiative coordinates the development of various community standards and formats for computational models in the life sciences. Over the past 10 years, COMBINE has brought together standard communities that have further developed and harmonized their standards for better interoperability of models and data. COMBINE 2019 was co-located with a stakeholder workshop of the European EU-STANDS4PM initiative that aims at harmonized data and model standardization for in silico models in the field of personalized medicine, as well as with the FAIRDOM PALs meeting to discuss findable, accessible, interoperable and reusable (FAIR) data sharing. This report briefly describes the work discussed in invited and contributed talks as well as during breakout sessions. It also highlights recent advancements in data, model, and annotation standardization efforts. Finally, this report concludes with some challenges and opportunities that this community will face during the next 10 years.

Specifications of standards in systems and synthetic biology: status and developments in 2020.

This special issue of the Journal of Integrative Bioinformatics presents papers related to the 10th COMBINE meeting together with the annual update of COMBINE standards in systems and synthetic biology.

Placental histopathology in sickle cell disease: A descriptive and hypothesis-generating study.

INTRODUCTION: Abnormal placental development is a unifying factor amongst many adverse pregnancy outcomes (APOs) in Sickle Cell Disease (SCD). Our aim was to describe placental histopathologic findings in women with SCD and their relationship with APOs, and to explore the association between antenatal sonographic findings and placental pathology. METHODS: Retrospective single-centre case series of all pregnant women with SCD (January 2000-December 2017), pregnancy beyond 20 weeks' gestation, and available placenta histopathology. APOs included intrauterine fetal death, early neonatal death, preterm birth, small for gestational age, and hypertensive disorders of pregnancy. Review of images for mid-pregnancy ultrasound and one proximal to delivery was completed, blinded to clinical outcomes and histopathology results. Gross and histopathologic findings were reviewed and characterized per published classification. RESULTS: Of 72 placentas, abnormalities were present in 69%, with Maternal Vascular Malperfusion (MVM) noted in 40%. APOs were encountered in 61% overall and in 79% of those with MVM. Neither SCD genotype nor severe maternal anemia had an influence on histopathologic placental features. Presence of high-resistance uterine artery waveforms at mid-trimester ultrasound was strongly associated with APOs and with abnormal findings on placental histopathology, most notably MVM. MVM was strongly associated with small for gestational age infants, preterm birth, and stillbirth. DISCUSSION: MVM is the predominant lesion in placentas of women with SCD and is strongly associated with APOs. Mid-trimester ultrasound can identify a subset of women at risk. Future research into advanced imaging modalities to aid in antenatal diagnosis alongside investigations of potentially beneficial therapies is needed.

Wikidata as a knowledge graph for the life sciences.

Wikidata is a community-maintained knowledge base that has been assembled from repositories in the fields of genomics, proteomics, genetic variants, pathways, chemical compounds, and diseases, and that adheres to the FAIR principles of findability, accessibility, interoperability and reusability. Here we describe the breadth and depth of the biomedical knowledge contained within Wikidata, and discuss the open-source tools we have built to add information to Wikidata and to synchronize it with source databases. We also demonstrate several use cases for Wikidata, including the crowdsourced curation of biomedical ontologies, phenotype-based diagnosis of disease, and drug repurposing.

Diagnostic Utility of Pathological Investigations in Late Gestation Stillbirth: A Cohort Study.

OBJECTIVE: Near term unexpected stillbirth is a common, complex diagnostic challenge. We review a large cohort of near term to term gestation unexpected fetal deaths to document the common patterns of pathology and evaluate the utility of various standard autopsy procedures. METHODS: A total of 123 perinatal autopsies consisting of 94 intrauterine fetal deaths (IUFDs) and 29 intrapartum deaths (IPDs) were reviewed. Deaths were classified according to the laboratory investigations establishing cause of death. RESULTS: Cause of death was attributable to placental pathology without autopsy in 55.3% of IUFD and 17% of IPD. Correlative findings at autopsy increased the ability to establish cause of death in 86.2% of IUFD and 62% of IPD. Histology was largely corroborative, with the brain, lungs, and heart demonstrating significant changes in 46%, 34.5%, and 13.8%, respectively. Microbiology was corroborative but demonstrated single organism growth in 6 of 29 cases of fatal acute chorioamnionitis. Newborn metabolic screening revealed only elevated thyroid-stimulating hormone levels in 3 cases, of questionable relevance. Aneuploidy was established by screening molecular studies in 5 IUFDs, all of which had external or visceral dysmorphism. Karyotype was established in 69 cases and was not contributory in any of the IPD: 3 IUFDs had changes of unknown significance. Cause of death was not established at autopsy in 9% of IUFD and 10% of IPD. DISCUSSION: This is the largest uniformly investigated cohort of late gestation unexpected fetal deaths studied. We confirm the importance of both placental and fetal autopsy in establishing cause of death. Autopsy histology, microbiology, and cytogenetics provide important but largely corroborative data.

BioModels-15 years of sharing computational models in life science.

Computational modelling has become increasingly common in life science research. To provide a platform to support universal sharing, easy accessibility and model reproducibility, BioModels (https://www.ebi.ac.uk/biomodels/), a repository for mathematical models, was established in 2005. The current BioModels platform allows submission of models encoded in diverse modelling formats, including SBML, CellML, PharmML, COMBINE archive, MATLAB, Mathematica, R, Python or C++. The models submitted to BioModels are curated to verify the computational representation of the biological process and the reproducibility of the simulation results in the reference publication. The curation also involves encoding models in standard formats and annotation with controlled vocabularies following MIRIAM (minimal information required in the annotation of biochemical models) guidelines. BioModels now accepts large-scale submission of auto-generated computational models. With gradual growth in content over 15 years, BioModels currently hosts about 2000 models from the published literature. With about 800 curated models, BioModels has become the world's largest repository of curated models and emerged as the third most used data resource after PubMed and Google Scholar among the scientists who use modelling in their research. Thus, BioModels benefits modellers by providing access to reliable and semantically enriched curated models in standard formats that are easy to share, reproduce and reuse.

Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2019.

This special issue of the Journal of Integrative Bioinformatics presents an overview of COMBINE standards and their latest specifications. The standards cover representation formats for computational modeling in synthetic and systems biology and include BioPAX, CellML, NeuroML, SBML, SBGN, SBOL and SED-ML. The articles in this issue contain updated specifications of SBGN Process Description Level 1 Version 2, SBML Level 3 Core Version 2 Release 2, SBOL Version 2.3.0, and SBOL Visual Version 2.1.