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[[Category: Annotation]]
= GO-CAMs and Noctua =
=Introduction=
*This documentation is presented in two parts:
==What is Noctua?==
** GO-CAM Principles
Noctua is a web-based, collaborative GO annotation editor. While creation of '''simple GO annotations''' is supported, Noctua was designed to enable connecting GO annotations, thus enriching the expressivity of the annotations and presenting a more complete picture of biology. Models produced with Noctua are called '''GO-CAM models'''. The overall goal is for each model to represent a unit that corresponds to a biological pathway. This document describes how to make GO-CAM models using Noctua.
** Noctua Curation Tool
 
== GO-CAM Principles ==
=== Standard GO Annotations and GO-CAM Models ===
==== Standard GO Annotations ====
 
[http://geneontology.org/docs/go-annotations/ GO annotations] have been a key component of GO since its inception.  Standard annotations are defined as an association between a gene and a biological concept from one of the [http://geneontology.org/docs/ontology-documentation/ three GO aspects]: Molecular Function (MF), Biological Process (BP), and Cellular Component (CC).  Standard annotations always contain a reference (either a published, peer-reviewed paper or internal GO reference) and an evidence code that indicates the type of experiment or method used to make the assertion.  Standard GO annotations may further be qualified using annotation extensions that provide additional biological context to a GO term using a relation from the [http://www.obofoundry.org/ontology/ro.html Relations Ontology (RO)] and a term from GO or an external ontology, e.g. [http://uberon.github.io/ UBERON].
 
==== GO-CAM Models ====
 
While standard GO annotations are very useful for discerning basic information about genes, they provide only a partial view of each gene's role in a larger biological context.  To provide more comprehensive annotation of genes and link their activities in a causal framework, the GO developed [http://geneontology.org/docs/gocam-overview/ GO-CAMs].  Using RO relations, GO-CAMs link GO annotations together with biological entities and external ontology terms to model how a  gene functions in the broader context of a biological process or pathway.  GO-CAMs thus provide structured descriptions of biological systems and allow for interrogation of causal events in biology through use of clearly defined, and consistently applied, semantics.
 
A summary of the GO-CAM model specifications is presented in Figure 1.  [[File:GO CAM figure from Google drive.png|thumb|center|Figure 1. GO-CAM Model Specifications|800px]]
 
The basic unit of a GO-CAM model is the Activity Unit, outlined on the left, which represents a set of standard GO annotations with select annotation extensions, e.g. the inputs and outputs of a molecular function. GO-CAM models are constructed by filling in as many pieces of relevant information in an Activity Unit as possible and then linking different Activity Units in a causal chain to model a biological process.  Thus, GO-CAM models use standard GO annotations as the foundation on which to build more comprehensive representations of biology.
 
=== Use of GO in GO-CAMs ===
 
==== Molecular Activities in GO-CAMs ====
 
* Wherever possible, curators should strive to select the single most granular GO Molecular Function (MF) term that best describes the overall activity of the gene, gene product, or protein-containing complex being annotated.
 
* If desired, individual "sub-functions" may be captured by using the 'part of' relation between the main MF and its sub-functions.
 
==== Biological Processes in GO-CAMs ====
 
* The ultimate aim of GO-CAMs is to create a suite of Biological Process (BP)-centric models that can be used to interrogate causal effects of molecular activities on one another as part of the execution of a larger BP.
 
* When annotating, curators should always think about the BP they are modeling and what MFs are 'part of' that BP.
 
* Additional relations between MFs and BPs, e.g. 'causally upstream of or within', can be used to capture experimental information that, in the future, will be incorporated into a more complete model of that process.
 
==== Cellular Components in GO-CAMs ====
 
* Cellular component annotations are intended to capture where the MF enabled by a gene, gene product, or protein-containing complex occurs.
 
* Cellular component annotations may be further qualified with cell, tissue, and organismal context if that information is germane to the process being modeled.
 
== Noctua: the Gene Ontology's GO-CAM Annotation Tool ==
[http://noctua.geneontology.org/ Noctua] is a web-based, collaborative [http://geneontology.org/ Gene Ontology (GO)] annotation tool developed by the GO Consortium.  Noctua can be used to create standard GO annotations as well as more expressive models of biological processes, known as [http://geneontology.org/docs/gocam-overview/ GO-CAMs (Gene Ontology Causal Activity Models)].  There are two types of user interface available in Noctua: 1) a form interface and 2) a graph interface.
 
=== System Requirements ===
Noctua is a web-based annotation tool and thus requires only a web browser to access and use. 
 
We have tested Noctua primarily with Chrome on a Mac operating system. 
 
Issues that arise using other browsers and operating systems may be reported on [https://github.com/geneontology/helpdesk/issues go-helpdesk]
 
=== User Account Setup ===
GO-CAMs can be browsed using Noctua, but no annotations can be created or edited unless a user has a registered account.
To create a new account, please email help@geneontology.org or enter a ticket on the [https://github.com/geneontology/helpdesk helpdesk repo in github]. 
 
Note that to create a Noctua account, you will need an [https://orcid.org/ ORCID] and a [https://github.com/ github account].  
 
Please allow 24 hours for your account to be created.
 
If you have any questions about user accounts, please contact help@geneontology.org
 
==Entities and Ontologies for Annotation==
=== Entities for Annotation ===
 
==== Genes and Gene Products ====
 
* The primary nodes in a GO-CAM model are the ACTIVITIES (Molecular Functions (MFs)) of genes, gene products, or protein-containing complexes.
 
* Every gene, gene product, and protein-containing complex annotated in GO-CAMs must be associated with a stable database identifier and represented either in a GPI (Gene Production Information) file (preferred), in an existing annotation file, e.g. a GAF (Gene Association File), or in the GO Cellular Component aspect.
 
* Curators should strive to annotate activities (MFs) to individual genes or gene products wherever possible.
 
==== Protein-Containing Complexes ====


==What is a simple GO annotation?==
* In GO-CAMs, curators should always try to assign each member of a protein-containing complex its specific activity (e.g. regulatory activity vs catalytic activity).  
A simple GO annotation is a gene product associated to a GO term, using an [http://wiki.geneontology.org/index.php/Guide_to_GO_Evidence_Codes evidence code] and a supporting reference (a primary research article, for example). The GO term may come from any of the three aspects of the GO: Molecular Function (MF), Biological Process (BP), or Cellular Component (CC). Gene products can correspond to proteins, complexes, or non-coding RNAs, and must be represented by a stable identifier.  Gene identifiers may serve as representative of one or more gene products.


==What is a GO-CAM model?==
* However, if the main activity of the protein-containing complex cannot be ascribed to a single subunit of the complex (e.g. RNA polymerase II activity), then the activity should be enabled by an appropriate protein-containing complex (e.g. a GO protein-containing complex), with each gene or gene product associated with that protein-containing complex with a 'part of' relation.
A GO-CAM model is a combination of simple GO annotations to produce a network of annotations ("model"). Minimally, a model must connect at least two simple annotations. The primary unit of biological modeling, or annotation, in GO-CAM is a molecular activity, e.g. protein kinase activity, of a specific gene product or complex.  A molecular activity is an activity carried out at the molecular level by a gene product; this is specified by a term from the GO MF ontology.  GO-CAM models are thus connections of GO MF annotations enriched by providing the appropriate context in which that function occurs.  All connections in a GO-CAM model, e.g. between a gene product and activity, two activities, or an activity and additional contextual information, are made using clearly defined semantic relations from the Relations Ontology.


===Providing context for molecular activities===
* Requests to add new entity identifiers to Noctua should be directed to help@geneontology.org
One major difference between simple annotations and GO-CAM models is that the former does not have explicit relations between the gene product being annotated and the GO term. In GO-CAM models, using defined, semantic relations allows us to capture how a gene product’s molecular function relates to other aspects of GO. GO-CAM explicitly defines the relationships between: 1) different aspects (MF, BP, CC) of each gene product as defined in GO, 2) the combined functions of different gene products (“pathways”), and 3) different systems of interacting functions (“modules”).


* a molecular activity may act upon another “target” molecule, this can be specified using a gene product identifier (for a protein or a gene) or a term from the ChEBI ontology (for a small molecule). In this case the MF is qualified with "has input'' [target_id].
=== Ontologies for Annotation ===
* a molecular activity ''occurs in'' a location: this includes cellular structures (described by a GO CC class (i.e. term), excluding the “macromolecular complex” branch), which can be further nested within larger structures using the appropriate cell and anatomy ontologies.
* a molecular activity is ''part of'' (i.e. helps to accomplish) a biological process, i.e. a biological program that also includes other molecular activities, which is described by a GO BP class (i.e. term). In turn, a biological process can be nested inside an even larger biological process.
* if the molecular activity ''occurs during'' a particular ''biological phase'' (e.g. a particular stage in organism development), this can be specified using a term from an appropriate ontology; i.e. any descendant of the term “GO:0044848 biological phase”.
* a molecular activity may also have upstream, causal roles with respect to a process, "acts upstream of" or its precise relationship to a process may not yet be known, in which case the relation would be "acts upstream of or within".  Each of these relations may further be qualified by indicating a positive or negative effect, e.g. "acts upstream of, positive effect".


===Linking different molecular activities===
==== Gene Ontology ====
Once the GO-CAM unit has been created (MF+BP+CC), these different units can be linked to each other to represent a causal activity model. The most common relations are ''directly (positively/negatively) regulates'' and ''provides input for'', but there are other relations of greater and lesser specificity, depending on what is known. ''Regulates'' should be used to denote biological control of a downstream activity. ''Provides input for'' should be used when there is no control, but an upstream function creates a molecular entity that is the target of the downstream function, such as in a metabolic pathway.
* The GO is used to annotate:
** Molecular Activities (MF)
** Biological Processes (BP)
** Cellular Component (CC)


===Incomplete GO-CAMs===
* To provide appropriate biological context to an annotation or an activity unit, additional ontologies may be used either in GO-CAM or in annotation extensions [link].
We recognize that the knowledge of biology is incomplete; in cases where some or most of these aspects are unknown, a model may still be constructed with details added as more information becomes available. Users should attempt to specify functions as fully as possible, but partial models are expected and still contribute to the GO knowledgebase.


=System Requirements=
====Relations Ontology====
*A web browser; Chrome is recommended.
Relations used in GO-CAM are a subset of Relations Ontology. These relations and their usage are described in the [[Annotation Relations]] page.


=Account Setup=
==Cell and Anatomy Ontologies==
Fill out the online [http://bit.ly/new-noctua-user new user form] and contact sjcarbon at lbl dot gov once complete. Propagating the metadata information may take a little time, so please do this as early as possible.  
* Describes the location where processes and functions occur.
* Describes the location of a GO cellular component.
* Add list
==Biological Phase and Life Stage Ontologies==
* Describes the temporal period during which processes and functions occur.
* Describes the temporal period during which a cellular component or anatomical entity exists.
* Add list
==Chemical Ontology (ChEBI) [link]==
* Can be used to capture inputs and outputs of processes and functions.
* GO-CAM uses the Chemical Entities of Biological Interest (ChEBI)
* Sequence Ontology [link]


To fill out this form, you need to have three things:
Requests to add ontologies to Noctua should be sent to help@geneontology.org
*an account on [https://github.com/ GitHub]
*an [http://orcid.org/ ORCID]
*organization/affiliation


If you don't already have a [https://github.com/ GitHub] or [http://orcid.org/ ORCID] account, please obtain these before continuing (note that in exceptional circumstances, it is possible to use Noctua without these).
== GO-CAM Workflow ==
* The ultimate goal for GO-CAMs is to create a knowledge graph whereby users can use the GO to traverse a causal representation of a biological system.
* To that end, curators should try, as much as possible, to make individual annotations in the context of the overall process being modeled.
* It can be very helpful to refer to a summary figure from a recent research article or review to help visualize a potential GO-CAM.
* When making a GO-CAM model, we suggesting these steps:
** What are the main activities (MFs) of each of the gene products in a model?
** How do those activities relate, in a causal chain, to each other?
** What processes are those activities involved in?
** Where do the activities occur?
* Even when annotating a single paper, try to incorporate as much of this workflow as possible.  This will make it easier, in the future, to build on existing models with new curation.


= Entities and Ontologies for Annotation =
== Noctua Users Manual ==
== Genes and Gene Products ==
* Noctua is accessed via: http://noctua.geneontology.org/
== Gene Ontology ==
== Contextual Ontologies ==
=== Cell and Anatomy Ontologies ===
=== Chemical Ontologies ===
=== Life Stage Ontologies ===
=== Sequence Ontologies ===


=Using Noctua=
=== Noctua Landing Page ===
* The Noctua landing page is the portal by which curators can browse or search and filter models. 
* It is also the starting point for curation (when logged in) and where individual GPAD and OWL files for a model can be downloaded.


==Noctua URL==
* By default, the Noctua landing page displays models by date, descending order, i.e. the most recently edited models are shown at the top of the list.  
* Go to http://geneontology.org/cam
* http://noctua.geneontology.org/


==Login==
*GO-CAM models may be viewed without logging in to Noctua, but if you wish to perform annotations or edits to a model, you must be logged in.
*To log in, click on the Login button in the upper right corner, and on the resulting page click on "Sign in with Github."  When you are signed in, press the "Return" button to return to the Noctua landing page.


==Searching Models==
[[File:NLP_home.png|thumb|center|upright=3.00|Noctua Landing Page]]
*The existing models list can be filtered using the search box just above the list of available models.
*Currently, models may be searched by title or the orcid of anyone who has contributed to the model.


==Editing an existing model==
*Click on the blue "Edit" button in the rightmost column of the model table. 


==Starting a new model==
==== Filtering Models ====
*Click on the blue "Create Noctua Model" button.
* There are two ways to filter GO-CAMs on the landing page:
#Click on the magnifying glass icon in the upper left
#Click on the metadata icons to the right of the model title in the table.  


==Creating an activity and its properties using the Noctua form==
*After either selecting an existing model to edit or starting a new one, you will be taken to the graph view by default. 
*To create new activities, you should use the “Noctua form” tool, available in the Workbench menu: Workbench -> Noctua form (Fig. 1)
[[File:Launch_noctua_activity_form.png|thumb|Fig. 1 Launching the Noctua form|400px]]
*This will launch a new browser tab with the Noctua form (Fig. 2)
[[File:Noctua_activity_form.png|thumb|Fig. 2 Noctua form.|400px]]
*In general, fill in as many fields as possible in the form, by typing in the field, and then selecting from the autocomplete suggestions by moving the mouse over your selection and clicking.
Tip: In the autocomplete, enter a space after a complete word, to narrow down the choices.
===Step 1. Create Model Metadata ===
*Enter a title for your model.
*Select a model "state". 
**By default, all models begin in a "Development" state.
**When ready, models may be moved to a "Production" state for publication by selecting "Production" from the drop-down list.
*Select an annotation group.
**Annotation groups are associated with curators in the users metadata file described above.
**By default, the first group associated with your entry in the metadata file is the group listed in the form.
**If you belong to multiple groups, you can select the appropriate group for your work from the drop-down list.


===Step 2. Create Annotations using the Function Description Form ===
[[File:Filtering options.png|thumb|center|upright=3.00|Filtering Options]]
====2.a. Enter gene product or macromolecular complex to be annotated====
By default, the form allows you to enter a single gene product.  Start typing, choices will appear, and then select the gene product.
Tip:
You can type in the gene symbol, e.g. Wnt3a or the unique identifier or accession, e.g. UniProtKB:P56704.  If necessary to narrow down the choices, type a space after the symbol, and enter the three letter code for the species (first letter from genus and two from species name, e.g. mmu for Mus musculus).  Each entry in the autocomplete will also show the associated unique database identifier or accession, so curators can confirm that they are selecting the appropriate entity for annotation.


====2.b. Enter the molecular function, evidence, and reference====
*These fields are required.  If you fill in the first field of any line, you need to add evidence and a reference.
*If the Molecular Function is known, enter the appropriate GO term, evidence code and reference.
*If the Molecular Function is unknown, but you are also making a Biological Process annotation, enter "molecular_function" and the same evidence and reference as the Biological Process annotation.
*If the Molecular Function is unknown, and there is no evidence for what the Molecular Function might be, enter "molecular_function" and the ND evidence code.


====2.c. Enter other fields (optional)====
===== Filtering with the Magnifying Glass =====
* For Molecular Function, the following "extensions" can optionally be added:
** has_input(molecule): fill in the "has input" field, evidence, and reference.
** happens_during(biological phase): fill in the "happens during" field, evidence, and reference.
* In addition, curators can add annotations to:
** Biological Process (the form assumes a part_of relation between the Molecular Function and Biological Process)
*** Additional BP part_of "extensions" can be made to provide contextual information to the BP term.
** Cellular Component (the form assumes an occurs_in relation between the Molecular Function and Cellular Component)
*** Additional part_of "extensions" can be made to provide contextual information about cell and/or tissue type.


We recommend that you fill in as many fields as possible before creating the activity, as after it is created, you will need to edit it from the graph canvas, which requires more steps to do.
Clicking on the magnifying glass opens up the menu of available filter options:


===Step 3. Add the new activity to a model===
#'''Ontology term''' (autocomplete)
Press the CREATE button.  A new activity will appear on the graph canvas (the main window)
#'''Gene product''' (autocomplete)
Tips:
#'''Reference'''
1. Each new activity will appear on the same part of the canvas, so if you add more than one activity you will need to move them around on the canvas (by clicking and dragging) to see the ones underneath.
## If entered as free-text, must be the full reference id, e.g. PMID:31884020 or doi:10.1016/j.ydbio.2019.12.010
2. If the CREATE button is grayed-out, there is some information missing from the form that you still need to fill in.  You can press the "why is the save button disabled?" for a list of missing fields.
## Can also use the drop-down prefix menu (and PMID look-up feature) by clicking on the =+ icon.
## Must press return after entering search string.
#'''Organism''' (drop-down list)
#'''Contributor''' (autocomplete and drop-down list)
#'''Groups''' (autocomplete and drop-down list)
#'''Exact date''' (enter YYYY-MM-DD/return or calendar, select/return)
#'''Date range''' (enter YYYY-MM-DD/return or calendar, select/return)
#'''Title''' (enter/return)
#'''State''' (drop-down list)


==Specifying the causal ordering of the activities==
[[File:Filter options menu.png|thumb|center|upright=3.00|Filtering Options]]
Once you have created at least two activities, you can specify the causal relations between them.  This is done on the graph canvas, by dragging from the blue circle of the upstream activity box, onto the downstream activity box (Fig. 3).  You can then select the relation.  Relations that are “direct” mean that there is a physical interaction mediating the effect on the downstream activity.
[[File:Noctua_linking_activities.png|thumb|Fig. 3 Making causal relations between activities.|400px]]
===Choosing the right causal relation between activities (MFs)===
====Direct Relations====
*If the upstream activity regulates the downstream activity through direct binding or by covalent modification, use the [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002629 '''directly positively regulates'''] or [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002630 '''directly negatively regulates'''] relation. Examples:
**Receptor ligand activity [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002333 '''enabled by'''] Wnt1 [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002629 '''directly positively regulates'''] receptor activity [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002333 '''enabled by'''] Fzd1 (''Wnt1 binds to the Fzd1 receptor and activates it'').
**Protein kinase activity enabled by MAP3K1 [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002629 '''directly positively regulates'''] protein kinase activity [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002333 '''enabled by'''] MAP2K1 (''MAP3K1 phosphorylates MAP2K1 and activates it'')
*If an upstream activity creates a molecule that is acted upon by the downstream activity, use [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002413 '''directly provides input for'''] relation. Examples:
**Glucose-6-phosphate dehydrogenase activity of GAPDH [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002413 '''directly provides input for'''] for phosphofructokinase activity of PFK2 (''the small molecule output from the GAPDH activity is acted upon by PFK2 as the next step in the metabolism of glucose'').
**(X phosphorylates Y, creating a molecule that is then acted upon by Z)


====Activities mediated by small molecule concentration====
=== Noctua Form and Graph Editors ===
Small molecules can be substrates ('''inputs''') of activities, created by activities ('''outputs''') or modulators of activities ('''regulatory''').  In these cases, GO-CAM models make explicit nodes representing small molecule concentrations.  To add a small molecule to a model, use the "Add Individual" item on the left of the graph canvas.  These should have CHEBI identifiers.
Noctua has three curation interfaces: 1) the [https://docs.google.com/document/d/1RNbr-2T6CSZfaYKDrom7259IK6ck82vZLThgymyNZ28 Noctua Visual Editor], 2) the Noctua Form and 3) the Noctua Graph Editor.
* '''a small molecule in a metabolic pathway''': in this case, connect the upstream activity (e.g. hexokinase activity) to its output (glucose-6-phosphate) using the [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002234 '''has_output'''] relation.  Then connect the small molecule to the downstream activity (e.g. phosphoglucose isomerase activity) using the [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002233 '''has_input'''] relation.
* '''regulation via a small molecule intermediate''': in this case the downstream activity must be a compound function, i.e. you will need to create '''TWO DISTINCT''' activities for the same gene product.  The first activity must be X binding, where X is the small molecule.  The second activity is the regulated activity.  Connect the upstream activity to the small molecule using [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002234 '''has_output'''], and the small molecule to the X binding activity using [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002233 '''has_input'''].  Then connect the first activity of the compound activity to the second one using a [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002629 '''directly positively regulates'''] or [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002630 '''directly negatively regulates'''] relation.
**ADCYA1 creates cAMP, which is an input to the cAMP binding function of PKCR1.  The cAMP binding function of PKCR1 then [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002630 '''directly negatively regulates'''] the protein kinase inhibitor activity of PKCR1.
**ADCHE1 breaks down acetylcholine, which directly binds to ACHR1 (acetylcholine binding) and activates its GPCR activity.


====Activities mediated by a biological process====
* The [https://docs.google.com/document/d/1RNbr-2T6CSZfaYKDrom7259IK6ck82vZLThgymyNZ28 Noctua Visual Editor] (VPE) is designed for curating GO-CAM models, i.e. models that include at least two activities/MFs linked by causal relations.
Similarly to mediation by small molecule concentration, the effects of some molecular activities on other activities are not strictly direct, but are mediated by a biological process.  Key examples are transcriptional regulation, regulation by ubiquitination and degradation, and regulation via membrane depolarization.  In these cases, create an instance of the mediating process (e.g. transcription), using the "Add Process" item on the left of the graph canvas.  Connect the upstream activity (e.g. transcription factor activity) to the mediating process (e.g. transcription) with [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002629 '''directly positively regulates'''], and the mediating process (transcription) to the downstream activity (the activity of the transcribed gene product) with [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002412 '''immediately causally upstream of'''].
* The Noctua Form is a structured annotation form that is recommended for creating 'standard' GO annotations.
* The Noctua Graph Editor is best suited for linking standard annotations together to create a causal model (GO-CAM).


====Indirect and unknown causal mechanisms====
*If the mechanism of the causal relation is not known, use the more general [https://www.ebi.ac.uk/ols/ontologies/ro/properties?iri=http%3A%2F%2Fpurl.obolibrary.org%2Fobo%2FRO_0002411 '''causally upstream of'''] relations (these can include a positive/negative effect, if known).


==Subfunctions: specifying more detail about molecular activities==
Sometimes, molecular activities are composed of distinct subfunctions, and those subfunctions may even be carried out in distinct locations, or by distinct subunits of a complex.  For example you may want to specify “hormone binding” in the “cytosol” as a subfunction of a nuclear receptor, that then activates (directly positively regulates) “transcription factor activity” in the “nucleus”.  To specify subfunctions, you will create new activities and link them to an activity that you have previously created that describes the overall function of the gene product (e.g. “nuclear receptor activity”).  Subfunctions (e.g. “hormone binding”) can be created using the Noctua form, but do not fill in the biological process field as it is the same as for the overall function.  Once the new activity is created, link it to the overall molecular function you created earlier, by dragging (on the graph canvas) from the subfunction activity (blue circle) to the overall activity, and selecting the “part of” relation.  You will then need to add evidence by clicking on the "part of" edge; a box will pop up; fill in the evidence fields and press the "Add" button.


==Editing the model==
{| class="wikitable"
Editing can currently be performed only on the graph canvas (the simple annoton editor form does not pick up any operations you have performed on the graph canvas).
!colspan="2" | Noctua Users Manual
Note that only one edit operation can be done at a time. To change something on the canvas, you will need to first ADD the correct part, and then DELETE the incorrect part, as separate operations. We recommend that you add first, so that you can transfer evidence from the incorrect part if necessary, by using the “clone other” operation.
|-
===Editing relations===
!rowspan="2" | Getting started
Relations can be removed by dragging the end of the relation arrow away from the box it connects to, into an empty part of the canvas. Relations can be added by clicking on the blue circle inside the upstream box, and dragging to the downstream box. Evidence for a relation can be edited by clicking on the relation arrow.
|[[Browsing and searching annotations and models]]
===Editing the type/label on a graph node===
|-
To edit a simple box on the graph (no colored bars indicating that it has multiple parts folded together for easy viewing), just click on the green square. To change it, first add the new term by filling in the field under “add type”, and clicking add. Then reopen the box again and delete the old term by clicking on the red “x” next to it.
|[[Login]]
===Editing types/labels that are inside a graph node===
|-
* To edit properties of an activity that are “folded” into the molecular activity box on the canvas, click on the green box in the corner of a box. Note that only one edit operation can be done at a time, so do not make more than one edit before pressing a button to save the edit. To change part of the annoton, you will need to first ADD the corrected part, and then DELETE the incorrect part, as separate operations.
!colspan="2" |Creating standard GO annotations
* To remove a property of the annoton, click the “x” next to it.
|-
* To edit the evidence, click on the “E” next to the part for which you want to edit evidence (e.g., the “E” next to enabled by is the evidence that the molecular function is enabled by the gene product).
!rowspan = "3" | Form Editor
==Making "traditional" (single aspect) GO annotations using Noctua==
|[http://wiki.geneontology.org/index.php/Noctua_Form_Molecular_Function Molecular Function]
===Molecular function annotation===
|-
* Use the "default" form
|[http://wiki.geneontology.org/index.php/Noctua_Form_Biological_Process Biological Process]
* Fill in the gene product field
|-
* Fill in the molecular function field, including evidence
|[http://wiki.geneontology.org/index.php/Noctua_Form_Cellular_Component Cellular Component]
* Optionally, the following "extensions" can be added:
|-
** has_input(molecule): fill in the "has input" field and evidence
!rowspan = "3" | Graph Editor
** happens_during(biological phase): fill in the "happens during" field and evidence
|[http://wiki.geneontology.org/index.php/Noctua_Graph_Molecular_Function Molecular Function]
** occurs_in(cellular component): fill in the "cellular component" field and evidence
|-
** part_of(biological_process): fill in the "biological process" field and evidence
|[http://wiki.geneontology.org/index.php/Noctua_Graph_Biological_Process Biological Process]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Graph_Cellular_Component Cellular Component]
|-
!colspan="3" |Adding contextual information (annotation extensions)
|-
!rowspan = "3" | Form Editor
|[http://wiki.geneontology.org/index.php/Noctua_Form_MF_Extensions Molecular Function]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Form_BP_Extensions Biological Process]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Form_CC_Extensions Cellular Component]
|-
!rowspan = "3" | Graph Editor
|[http://wiki.geneontology.org/index.php/Noctua_Graph_MF_Extensions Molecular Function]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Graph_BP_Extensions Biological Process]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Graph_CC_Extensions Cellular Component]
|-
!colspan="2" | Editing annotations
|-
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Editing_in_form Form Editor]
|-
|[[Graph Editor]]
|-
!colspan="2" | Creating GO-CAMs
|-
!rowspan = "2" | Creating an activity unit
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Creating_an_Activity_Unit_in_Form Form Editor]
|-
|[[Graph Editor]]
|-
!rowspan = "2" | Linking Activities
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Linking_Activities_in_Form Form Editor]
|-
|[[Graph Editor]]
|-
!colspan = "2" | Model metadata
|-
!rowspan = "3" | Model titles
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_General_Guidelines_for_Model_Titles General Guidelines]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Naming_Models_in_Form Form Editor]
|-
|[[Graph Editor]]
|-
!rowspan = "2" | Releasing models to production
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Making_Models_Production_in_Form Form Editor] Form Editor]
|-
|[[Graph Editor]]
|-
!rowspan = "7" | Other tips and tricks
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Adding_NOT_Qualifer_in_Form Adding a NOT qualifier to an annotation]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Importing_existing_annotations Importing existing annotations]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Changing_annotation_group Changing annotation group]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Model_validation Model validation]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Running_the_reasoner Running the reasoner]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Viewing_GPAD_export Viewing GPAD export]]
|-
|[http://wiki.geneontology.org/index.php/Noctua_Manual:_Using_templates Using templates]
|-
|}


===Cellular component annotation===
=== Noctua Annotation Review ===
This is for annotations of where a gene product has been observed (but is not known to be active). Note that these annotations have a different meaning than using the default form: the gene product has been observed in the CC, but may or may not be active there.
Documentation on how to use the Noctua Annotation Review workbench is [https://docs.google.com/document/d/1Yo2O7LWj1wdRGbbOlaxX_AFDl99T-P59JOf5YoebX0Q/edit#heading=h.jjddl63ap4eh here].
* Use the "CC only" version of the form (select by clicking on the drop-down on the right that says "DEFAULT").
* Fill in the gene product field.
* Fill in the cellular component field with the desired GO term, and evidence.
* * Optionally, one or both of the following "extensions" can be added:
** part_of (a larger cellular component)
** part_of (cell type)
** part_of (anatomy)
 
===Biological process annotation===
This is for annotations that assert a relationship to a BP other than part_of, e.g. for regulates or causally upstream of relations.
* Use the "BP only" version of the form (select by clicking on the drop-down on the right that says "DEFAULT").
* Fill in the gene product field.
* Choose the relation between the gene product and the BP.
* Fill in the biological process field with the desired GO term, and evidence.
* Optionally, one or both of the following "extensions" can be added:
** part_of (cell type)
** part_of (anatomy)
---------


==Naming your Model and Saving your Work Using the Graphical Editor==
=== Model Copy ===
* Noctua has a model copy functionality that allows users to copy an entire model, minus the evidence.
* Model copy can help curators make efficient use of existing models to create new content.
* More details on model copy and how to use it can be found [https://docs.google.com/document/d/17qlOwSOov-hTKt1wxcyhF1M0XzfQG-r2N6RmhaNj2-E here].


While you create or edit your model, you will see an asterisk appear around the "Untitled" text in your browser tab. The asterisk indicates that your work is not yet saved, and the "Untitled" indicates that you have not yet named your model. To name your model and save your work, click on the drop-down menu under the Model heading and select the "Edit Annotations" option. In the "Title" section, add a title for your model. The beginning of the title will now appear in the browser tab. To save your work, click on the Model heading again and select the "Save" option. Your work is now saved and the asterisk in the tab will disappear. Save your work often while editing!
== Noctua Maintenance ==
Tip:
* The Noctua curation tool undergoes routine maintenance on the second and fourth Thursdays of each month from ~4pm - 7pm PDT.
If your model already has a name, you will need to delete the name first, before you can rename it. Follow the same instructions above, but press the Delete button next to the name instead
* During these maintenance outages the following tasks are typically performed:
---------
** Ontology updates:
*** incorporate the latest versions of all ontologies used in Noctua, including NEO (Noctua Entity Ontology)
** Model updates:
*** replace obsolete ontology terms if there is a 'replaced by' value
*** replace ontology terms if usage has changed
*** delete any models marked with state 'delete'
** Software updates:
*** Incorporate bug fixes
*** Add new features
* Noctua maintenance outage reminders are sent out on the go-consortium mailing list ~24 hrs. prior to the outage.
* For each outage, a list of specific tasks is enumerated in a ticket on the noctua github repo.


==How to Make a Model Public (Production)==
*By default, new models are considered under "development" meaning that curators may work on the model, but the model, and any GO annotations derived from it, are not available for public consumption
*This allows curators to work on a model over a period of time, perhaps review them with colleagues or experts in the field, and then publish them to the GO or other web sites.
*When ready, curators have the ability to explicitly change the production status of their model.
*To do this in the Simple annoton editor, select "Production" from the State drop-down to the right of the model title.
*To do this, in the graphical editor, click on the Model drop down menu and select "Edit annotations" from the list.
**Under the "Annotation state" section, delete the "Development" status.
**Return to the Model drop-down, select "Edit annotations" from the list and under "Annotation state" select "Production" from the drop-down list.
**Production - model will be available for viewing on the GO web site and annotation files available for consumption


==Providing Feedback==
[[Category: Annotation]]
*Bug reports and requests for new features should be entered on the [https://github.com/geneontology/noctua/issues GO's Noctua issue tracker on GitHub].
*Before entering a new ticket, please be sure to search the tracker to see if the bug or feature request has not already been reported!

Latest revision as of 11:36, 8 January 2024

GO-CAMs and Noctua

  • This documentation is presented in two parts:
    • GO-CAM Principles
    • Noctua Curation Tool

GO-CAM Principles

Standard GO Annotations and GO-CAM Models

Standard GO Annotations

GO annotations have been a key component of GO since its inception. Standard annotations are defined as an association between a gene and a biological concept from one of the three GO aspects: Molecular Function (MF), Biological Process (BP), and Cellular Component (CC). Standard annotations always contain a reference (either a published, peer-reviewed paper or internal GO reference) and an evidence code that indicates the type of experiment or method used to make the assertion. Standard GO annotations may further be qualified using annotation extensions that provide additional biological context to a GO term using a relation from the Relations Ontology (RO) and a term from GO or an external ontology, e.g. UBERON.

GO-CAM Models

While standard GO annotations are very useful for discerning basic information about genes, they provide only a partial view of each gene's role in a larger biological context. To provide more comprehensive annotation of genes and link their activities in a causal framework, the GO developed GO-CAMs. Using RO relations, GO-CAMs link GO annotations together with biological entities and external ontology terms to model how a gene functions in the broader context of a biological process or pathway. GO-CAMs thus provide structured descriptions of biological systems and allow for interrogation of causal events in biology through use of clearly defined, and consistently applied, semantics.

A summary of the GO-CAM model specifications is presented in Figure 1.

Figure 1. GO-CAM Model Specifications

The basic unit of a GO-CAM model is the Activity Unit, outlined on the left, which represents a set of standard GO annotations with select annotation extensions, e.g. the inputs and outputs of a molecular function. GO-CAM models are constructed by filling in as many pieces of relevant information in an Activity Unit as possible and then linking different Activity Units in a causal chain to model a biological process. Thus, GO-CAM models use standard GO annotations as the foundation on which to build more comprehensive representations of biology.

Use of GO in GO-CAMs

Molecular Activities in GO-CAMs

  • Wherever possible, curators should strive to select the single most granular GO Molecular Function (MF) term that best describes the overall activity of the gene, gene product, or protein-containing complex being annotated.
  • If desired, individual "sub-functions" may be captured by using the 'part of' relation between the main MF and its sub-functions.

Biological Processes in GO-CAMs

  • The ultimate aim of GO-CAMs is to create a suite of Biological Process (BP)-centric models that can be used to interrogate causal effects of molecular activities on one another as part of the execution of a larger BP.
  • When annotating, curators should always think about the BP they are modeling and what MFs are 'part of' that BP.
  • Additional relations between MFs and BPs, e.g. 'causally upstream of or within', can be used to capture experimental information that, in the future, will be incorporated into a more complete model of that process.

Cellular Components in GO-CAMs

  • Cellular component annotations are intended to capture where the MF enabled by a gene, gene product, or protein-containing complex occurs.
  • Cellular component annotations may be further qualified with cell, tissue, and organismal context if that information is germane to the process being modeled.

Noctua: the Gene Ontology's GO-CAM Annotation Tool

Noctua is a web-based, collaborative Gene Ontology (GO) annotation tool developed by the GO Consortium. Noctua can be used to create standard GO annotations as well as more expressive models of biological processes, known as GO-CAMs (Gene Ontology Causal Activity Models). There are two types of user interface available in Noctua: 1) a form interface and 2) a graph interface.

System Requirements

Noctua is a web-based annotation tool and thus requires only a web browser to access and use.

We have tested Noctua primarily with Chrome on a Mac operating system.

Issues that arise using other browsers and operating systems may be reported on go-helpdesk

User Account Setup

GO-CAMs can be browsed using Noctua, but no annotations can be created or edited unless a user has a registered account.

To create a new account, please email help@geneontology.org or enter a ticket on the helpdesk repo in github.

Note that to create a Noctua account, you will need an ORCID and a github account.

Please allow 24 hours for your account to be created.

If you have any questions about user accounts, please contact help@geneontology.org

Entities and Ontologies for Annotation

Entities for Annotation

Genes and Gene Products

  • The primary nodes in a GO-CAM model are the ACTIVITIES (Molecular Functions (MFs)) of genes, gene products, or protein-containing complexes.
  • Every gene, gene product, and protein-containing complex annotated in GO-CAMs must be associated with a stable database identifier and represented either in a GPI (Gene Production Information) file (preferred), in an existing annotation file, e.g. a GAF (Gene Association File), or in the GO Cellular Component aspect.
  • Curators should strive to annotate activities (MFs) to individual genes or gene products wherever possible.

Protein-Containing Complexes

  • In GO-CAMs, curators should always try to assign each member of a protein-containing complex its specific activity (e.g. regulatory activity vs catalytic activity).
  • However, if the main activity of the protein-containing complex cannot be ascribed to a single subunit of the complex (e.g. RNA polymerase II activity), then the activity should be enabled by an appropriate protein-containing complex (e.g. a GO protein-containing complex), with each gene or gene product associated with that protein-containing complex with a 'part of' relation.
  • Requests to add new entity identifiers to Noctua should be directed to help@geneontology.org

Ontologies for Annotation

Gene Ontology

  • The GO is used to annotate:
    • Molecular Activities (MF)
    • Biological Processes (BP)
    • Cellular Component (CC)
  • To provide appropriate biological context to an annotation or an activity unit, additional ontologies may be used either in GO-CAM or in annotation extensions [link].

Relations Ontology

Relations used in GO-CAM are a subset of Relations Ontology. These relations and their usage are described in the Annotation Relations page.

Cell and Anatomy Ontologies

  • Describes the location where processes and functions occur.
  • Describes the location of a GO cellular component.
  • Add list

Biological Phase and Life Stage Ontologies

  • Describes the temporal period during which processes and functions occur.
  • Describes the temporal period during which a cellular component or anatomical entity exists.
  • Add list

Chemical Ontology (ChEBI) [link]

  • Can be used to capture inputs and outputs of processes and functions.
  • GO-CAM uses the Chemical Entities of Biological Interest (ChEBI)
  • Sequence Ontology [link]

Requests to add ontologies to Noctua should be sent to help@geneontology.org

GO-CAM Workflow

  • The ultimate goal for GO-CAMs is to create a knowledge graph whereby users can use the GO to traverse a causal representation of a biological system.
  • To that end, curators should try, as much as possible, to make individual annotations in the context of the overall process being modeled.
  • It can be very helpful to refer to a summary figure from a recent research article or review to help visualize a potential GO-CAM.
  • When making a GO-CAM model, we suggesting these steps:
    • What are the main activities (MFs) of each of the gene products in a model?
    • How do those activities relate, in a causal chain, to each other?
    • What processes are those activities involved in?
    • Where do the activities occur?
  • Even when annotating a single paper, try to incorporate as much of this workflow as possible. This will make it easier, in the future, to build on existing models with new curation.

Noctua Users Manual

Noctua Landing Page

  • The Noctua landing page is the portal by which curators can browse or search and filter models.
  • It is also the starting point for curation (when logged in) and where individual GPAD and OWL files for a model can be downloaded.
  • By default, the Noctua landing page displays models by date, descending order, i.e. the most recently edited models are shown at the top of the list.


Noctua Landing Page


Filtering Models

  • There are two ways to filter GO-CAMs on the landing page:
  1. Click on the magnifying glass icon in the upper left
  2. Click on the metadata icons to the right of the model title in the table.


Filtering Options


Filtering with the Magnifying Glass

Clicking on the magnifying glass opens up the menu of available filter options:

  1. Ontology term (autocomplete)
  2. Gene product (autocomplete)
  3. Reference
    1. If entered as free-text, must be the full reference id, e.g. PMID:31884020 or doi:10.1016/j.ydbio.2019.12.010
    2. Can also use the drop-down prefix menu (and PMID look-up feature) by clicking on the =+ icon.
    3. Must press return after entering search string.
  4. Organism (drop-down list)
  5. Contributor (autocomplete and drop-down list)
  6. Groups (autocomplete and drop-down list)
  7. Exact date (enter YYYY-MM-DD/return or calendar, select/return)
  8. Date range (enter YYYY-MM-DD/return or calendar, select/return)
  9. Title (enter/return)
  10. State (drop-down list)
Filtering Options

Noctua Form and Graph Editors

Noctua has three curation interfaces: 1) the Noctua Visual Editor, 2) the Noctua Form and 3) the Noctua Graph Editor.

  • The Noctua Visual Editor (VPE) is designed for curating GO-CAM models, i.e. models that include at least two activities/MFs linked by causal relations.
  • The Noctua Form is a structured annotation form that is recommended for creating 'standard' GO annotations.
  • The Noctua Graph Editor is best suited for linking standard annotations together to create a causal model (GO-CAM).


Noctua Users Manual
Getting started Browsing and searching annotations and models
Login
Creating standard GO annotations
Form Editor Molecular Function
Biological Process
Cellular Component
Graph Editor Molecular Function
Biological Process
Cellular Component
Adding contextual information (annotation extensions)
Form Editor Molecular Function
Biological Process
Cellular Component
Graph Editor Molecular Function
Biological Process
Cellular Component
Editing annotations
Form Editor
Graph Editor
Creating GO-CAMs
Creating an activity unit Form Editor
Graph Editor
Linking Activities Form Editor
Graph Editor
Model metadata
Model titles General Guidelines
Form Editor
Graph Editor
Releasing models to production Form Editor Form Editor]
Graph Editor
Other tips and tricks Adding a NOT qualifier to an annotation
Importing existing annotations
Changing annotation group
Model validation
Running the reasoner
Viewing GPAD export]
Using templates

Noctua Annotation Review

Documentation on how to use the Noctua Annotation Review workbench is here.

Model Copy

  • Noctua has a model copy functionality that allows users to copy an entire model, minus the evidence.
  • Model copy can help curators make efficient use of existing models to create new content.
  • More details on model copy and how to use it can be found here.

Noctua Maintenance

  • The Noctua curation tool undergoes routine maintenance on the second and fourth Thursdays of each month from ~4pm - 7pm PDT.
  • During these maintenance outages the following tasks are typically performed:
    • Ontology updates:
      • incorporate the latest versions of all ontologies used in Noctua, including NEO (Noctua Entity Ontology)
    • Model updates:
      • replace obsolete ontology terms if there is a 'replaced by' value
      • replace ontology terms if usage has changed
      • delete any models marked with state 'delete'
    • Software updates:
      • Incorporate bug fixes
      • Add new features
  • Noctua maintenance outage reminders are sent out on the go-consortium mailing list ~24 hrs. prior to the outage.
  • For each outage, a list of specific tasks is enumerated in a ticket on the noctua github repo.