The COVID-19 explorer—An integrated, whole patient knowledge model of COVID-19 disease

Since early 2020 the COVID-19 pandemic has paralyzed the world, resulting in more than half a billion infections and over 6 million deaths within a 28-month period. Knowledge about the disease remains largely disjointed, especially when considering the molecular mechanisms driving the diversity of clinical manifestations and symptoms. Despite the recent availability of vaccines, there remains an urgent need to develop effective treatments for cases of severe disease, especially in the face of novel virus variants. The complexity of the situation is exacerbated by the emergence of COVID-19 as a complex and multifaceted systemic disease affecting independent tissues and organs throughout the body. The development of effective treatment strategies is therefore predicated on an integrated understanding of the underlying disease mechanisms and their potentially causative link to the diversity of observed clinical phenotypes. To address this need, we utilized a computational technology (the Dataome platform) to build an integrated clinico-molecular view on the most important COVID-19 clinical phenotypes. Our results provide the first integrated, whole-patient model of COVID-19 symptomatology that connects the molecular lifecycle of SARS-CoV-2 with microvesicle-mediated intercellular communication and the contact activation and kallikrein-kinin systems. The model not only explains the clinical pleiotropy of COVID-19, but also provides an evidence-driven framework for drug development/repurposing and the identification of critical risk factors. The associated knowledge is provided in the form of the open source COVID-19 Explorer (https://covid19.molecularhealth.com), enabling the global community to explore and analyze the key molecular features of systemic COVID-19 and associated implications for research priorities and therapeutic strategies. Our work suggests that knowledge modeling solutions may offer important utility in expediting the global response to future health emergencies.


1. About MH Corona Explorer
MH Corona Explorer is an interactive bioinformatics software application for analyzing the effects of the SARS-CoV-2 virus, from the symptom level down to the protein/gene level.
You can use it to understand the diseases and symptoms triggered by the virus, and to understand potential treatments (drugs) and vaccines, by looking at how and where they interact in the cellular mechanisms.
The core data in the MH Corona Explorer comes from analysis of over 10,000 relevant publications by MH bioinformaticians, curators, and medical experts.
MH Corona Explorer visualizes the mechanisms underlying the SARS-CoV-2 virus in eight interactive screens: • Organs & Symptoms: explore a 3D human model for an overview of organs, diseases, and symptoms, and follow links to the underlying biomedical models.
• Pathogenic Mechanisms: explore an interactive network of organs, symptoms, mechanisms, and signaling axes.
• Disease Model: understand central mechanisms behind cell damage, even in cells not directly infected by the virus.
• Expanded Model: visualize pathways, molecular mechanisms, and biological systems affected by the virus.
• Symptom Mechanisms: interactive list of symptom mechanisms and the related genes and proteins.
• Functional Mechanisms: list of mechanisms triggered by the SARS-CoV-2 virus, and the related genes and proteins.
• Publications: Browse over 300 publications underlying the MH Corona Explorer.
• Terminology Reference: a resource that links terminology from the disparate disciplines of biology and medicine.Symptoms and syndromes: For the sake of simplicity, to reduce the number of terms used, we use the term "symptom" for individual symptoms (e.g.thrombosis) as well as for groups of symptoms often referred to as a syndrome.We use "disease" to define a group of symptoms with a specific cause.
Mechanisms focus on key biological mechanisms (e.g.coagulation), for this reason they do not share the same name as the symptoms they cause.For example, while "pneumonitis" is the term used to describe a symptom of lung inflammation, the term used for this mechanism is "inflammatory signaling".

Gene names and molecule names:
In some cases, different names are used in parallel to denote the same genes.Here are some common examples: the gene name DABK is a synonym for the molecule [des-Arg9] BK, the gene name BDKRB1 is a synonym for B1R, often used in biological models, and KNG1 is a synonym of HK.Where feasible, to facilitate understanding, we list both versions.
? Help texts and legends: Click the question mark symbol (?) at the top right of each screen to access an explanation of the screen as well as an explanatory list of any symbols used.

Navigating with a mouse, trackpad, or touchpad
With a touchpad, you can also swipe with two fingers to zoom in and out.

Navigating with the computer keyboard
To move in smaller steps, hold the shift key while using the above controls.

Navigating with the built-in toolbars
Here is an overview of the available tools.As the toolbars are task-sensitive, the entire selection of tools is not visible on the screen at any one time.

Detailed Symptom Mechanism
Here is an example of a detailed Symptom Mechanism.

Functional Mechanisms tab
The Functional Mechanisms tab lists the mechanisms involved in SARS-CoV-2 and provides links to associated pathways.This information is curated by MH and includes links to underlying publications.

Detailed Functional Mechanism
Here is an example of a detailed Functional Mechanism.

Publications tab
The Publications tab provides a list of relevant publications curated by MH experts and used to create all models and mechanisms.The default sort order of the Publications list is by PMID, with the most recent publication (the largest PMID number) first.

Terminology Reference tab
Find associated terms from the domains of biology and medicine using the search function.The terms are grouped by organ and sorted from head to toe.Where can I find more information?
For further details see "Unraveling the Multiple Manifestations of COVID-19 using Augmented Clinico-Molecular Disease Modeling" (submitted for publication) or contact us at corona@molecularhealth.com

Contact Molecular Health
You can contact the Molecular Health Customer Service team by email at corona@molecularhealth.com.
Mechanisms tab On the Pathogenic Mechanisms tab, you can explore eight interactive networks showing different perspectives on the mechanisms involved in an infection with the SARS-CoV-2 virus.Scroll through the screens to see organ-specific disease manifestations, pathogenic mechanisms, and associated symptoms.You can visualize how individual entities interact along signaling axes, and navigate to detailed information on each mechanism.To avoid overcrowding the network diagram, inflammation is not shown.Model tab The Disease Model tab, Cell mechanism screen shows key mechanisms of the virus that cause damage at the cell level.The Disease model tab, Evidence screen shows short and long term consequences observed in a group of SARS-CoV-2 patients.The Mechanisms are described in detail pressing the Button « Show Description » Model tab The Expanded Model tab shows the systems and pathways involved in SARS-CoV-2, and provides links to detailed visualizations of the pathways involved in the underlying Symptom Mechanisms and Functional Mechanisms.tab shows the mechanisms involved in SARS-CoV-2 and provides links to associated pathways.This information is curated by MH and includes links to underlying publications.Molecular Health GmbH Kurfuersten-Anlage 21, 69115 Heidelberg, Germany T +49 6221 43851-0 germany@molecularhealth.com Better data.Better insights.Better outcomes.molecularhealth.com This COVID-19 disease model was developed as a collaboration between the translational research organization of the Institute of Regenerative Medicine of the Zürich University and Molecular Health GmbH, Heidelberg, experts in data-driven precision medicine.The disease model is based on the Augmented Clinico-Molecular Disease Modeling technology (aCMDM), linking key molecular entities to COVID-19 pathophysiology and to disease symptoms (e.g., dry cough, myalgia, anosmia, dysgeusia/ageusia, new onset diabetes, etc.), severe manifestations (e.g., ARDS, ALI, lung fibrosis, cardiovascular complications), and outcome-and severity-associated risk factors (e.g., age, sex, smoking, comorbidities).