1.What is PhenoTips?
As part of the RD-Connect Genome-Phenome Analysis Platform, we will set up each of the associated projects with an account in the clinical database at PhenoTips.
Users will be expected to enter the phenotypic data which has been collected for each of the participants, even unaffected individuals (who just need to have a note to say they are unaffected), whose samples are being sent for sequencing as part of the project.
In order to do this you need to follow the instructions in this section.
Once you have been verified and registered with RD-Connect, you will receive your username and password.
Navigate to https://platform.rd-connect.eu/phenotips/ and log in with these credentials.
CHANGING YOUR PASSWORD
The first time you log in, you can change your password to something more memorable. To do this, click on your name at the top right of the screen, select Preferences on the left hand menu and choose Change Password.
3.Landing page explained
Whenever you want to return to the starting page, click the PhenoTips logo in the top left corner of the screen. This takes you to the home page which acts as a dashboard for the various features of PhenoTips.
Here you can see who is a member of each group and how many cases belong to each. This is important for when you come to share your data with others.
Groups always have the format <institution acronym>–<PI surname> (e.g. unew-horvath).
Clicking on a group will open a new page with more details.
This lists participant records you have already created.
You can open a record by clicking on it, and also sort the records by the ID, creator or creation date.
PATIENTS SHARED WITH ME
This lists participant records created by other users who have added you, or a group of which you are a member, as a collaborator.
This lists Families that you have created using the Pedigree Editor. This will be covered later in the guide and is done when you create new participant records.
FAMILIES SHARED WITH ME
Lists Families created by other users who have added you, or a group of which you are a member, as a collaborator.
4.How to create the patient records
To enter new participant data you can either click on NEW PATIENT at the top of the MY PATIENTS window, or you can hover over the + Create… dropdown menu at the top of the screen and select New patient.
We use the Human Phenotype Ontology (HPO) to record phenotypes for participants in order to match between cases.
We have grouped some HPO terms that are relevant to particular diseases into Studies, so that if the record you are creating is relevant to one of the Study forms, you can select that and it will list the phenotypic terms appropriate for that case.
Select the disease (Study) form you wish to use, this will determine if the form will have sections specific to that disease, otherwise choose None, and click the Create button at the bottom of the window – a blank record will appear.
Confirm that consent has been taken for NGS and for clinical data sharing by checking the boxes at the top of the form – if the consent is not in place, data can still be entered but the patient should be re-consented and the boxes checked once this has been done.
Enter your external ID code for this patient record in the Identifier field. This must match with the ID provided for the raw sequencing data so that the PhenoTips record can be matched with the appropriate data. Also make a note of the PhenoTips ID (top left of the window) for your records so that you know which PhenoTips ID corresponds to which of your own IDs.
Continue through the form entering the patient information as required. For some fields you can click the ? or ! icon for further information.
You can add multiple ethnicity descriptions for each parent; as you type a list of terms will appear for you to choose from.
Choose Y (affected) or N (unaffected) for Clinical status. This is mandatory so that we can differentiate between affected and unaffected individuals.
Now work through the Inheritance, Progression and Onset data. Indented descriptions are subcategories of those above. If you click on the little ‘info’ icon, a definition will pop-up.
Work through the rest of the form clicking on the headers to open out the sections of the form.
Where a triangle exists beside an observed phenotype, clicking on it will reveal sub-categories. Some of the sections may or may not be visible depending on the Study you selected.
5.Using the Pedigree Editor
You must now enter the known relations of the participant by clicking on Draw pedigree. If you do not know of any of the relations, please create a pedigree anyway by using the first available template that pops up for a single individual (see below). This is important for us to monitor the number of index cases and families in the system to make it more effective.
A window will pop up and you should select Create a new family, unless the family already exists in the system.
Select the most appropriate template for the family, or click on Import to pull in existing data if it is in one of the supported data formats.
If you hover over one of the nodes in the pedigree, you can add more relatives by selecting the relevant branch that ends with a blue button
Clicking on a node will open up a window where you can enter information about that family member; click on Create new to make a new record for this person
Next click on the PhenoTips ID (make a note of this for your records) and you will be taken to the new, blank record. Click Edit and fill in all the information for this record, making sure to click Save when done.
You can then close this browser window as the Pedigree Editor will still be open in a separate window in your browser. Continue to create records for all other family members in the same way.
Once the pedigree is complete, click Save and then Close to return to the original index case record.
6.Entering HPO terms
If the person is an unaffected relation, please tick the This patient is clinically normal checkbox and move on to the next section.
You may search for phenotypic information not included in the form by typing a feature in the Quick Phenotype Search box. Suggestions from the ontology will appear and you can choose the most appropriate one.
You can also browse the HPO terms in the form itself, clicking on a category to open up further choices, and the blue triangular symbols to expand the hierarchy of HPO terms further.
We ask that you submit a minimum of 7 HPO terms here, if possible, as any less renders the record less useful when using the analysis platform to compare and match cases.
Under Diagnosis you can type in any confirmed diagnosis and choose from the pop-up OMIM descriptions. You may also select from the suggested diagnoses which have been generated based on your entered phenotype data.
Click on the Save button at the very top of the page to save your record.
8.After the case has been analysed
Once the case has been analysed through the RD-Connect Genome-Phenome Analysis Platform (https://platform.rd-connect.eu/genomics/ ), you can enter information concerning its resolution status (solved, unsolved or with candidate gene/variant(s) under functional studies).
Use the Analysis status section to keep track of your analysis stage:
Press the + button to update your entry and enter the current analysis status:
Save the record. You will be able to see and update this information at any time in this same section.
8.1.After the case has been solved
Once a case has been analysed and solved, the causative(s) variant(s) should be identified and TAG in the RD-Connect Genome-Phenome Analysis platform and the case status updated in PhenoTips. Therefore the following 3 steps should be done:
- Identify and TAG the causative variant in the genomic platform
- Enter the corresponding OMIM and ORDO codes
- State the case as “Solved”
1. IDENTIFY AND TAG THE CAUSATIVE VARIANT
To identify and TAG the corresponding causative variant(s), you should go to the RD-Connect Genome-Phenome analysis platform (https://platform.rd-connect.eu/genomics/ ), and run the query with the addequate filters to get the causative variant(s) in the results section.
We suggest to filter by the “gene name” to restrict the query; as you type a list of genes will appear for you to choose from.
Then select the causative variant from the result section and click the TAG button
A form will appear with different dropdowns to fill in.
We strongly recommend you to follow the ACMG standards and guidelines for the interpretation of sequence variants (PMID:25741868) and to fill in the clinical significance of the variant in the form. Intervar is a bioinformatics software tool for clinical interpretation of genetic variants by the ACMG/AMP 2015 guideline that might help you in this process (http://wintervar.wglab.org/). This information will be stored in the RD-Connect database and will be accessible through the data submission module.
Once TAGed, you will be able to consult the information entered (from you or other RD-Connect users that might have TAG the variant) selecting the variant and the “candidate” tab in the upper pannel (the number of users that have tagged the variant appear in red next to the TAG button):
2. ADD OMIM AND ORDO CODES
Go to PhenoTips, select the solved index case you want to update either by browsing all your patients or entering the corresponding PhenoTips ID in the search box.
Click on EDIT at the top of the window to enter the edition view
Open the DIAGNOSIS section to enter the corresponding OMIM and ORDO descriptions; as you type a list of terms will appear for you to choose from.
3. STATE THE CASE AS SOLVED
Open the CASE RESOLUTION section and tick the case as solved
Remember to save your changes before leaving the page.
8.2.Data sharing and matchmaking
RD-Connect GPAP has integrated different tools that enable to match challenging patient diagnostic cases with other patients in a federated network of collaborating
projects and centres:
- Matchmaker Exchange
- Patient matching through PhenomeCentral
- Beacon network
Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to RD gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). For more information visit https://www.matchmakerexchange.org/
To allow patient internal and external matching through MME you need to follow the following steps:
BEFORE STARTING THIS PROCESS ENSURE THAT YOU HAVE THE APPROPIATE PATIENT INFORMED CONSENT FOR DATA SHARING.
1. Set the patient as matchable in the data management module
If you have not previously selected the patient as matchable during the submission data process please go the the RD-Connect data management module and change the participant MME status to matchable.
Access your patient information view selecting Participant in the Manage your RD-Connect section at the bottom of the page
Select the IDs of the patients you want to allow matchmaking
and change their status clicking on select participant as matchable in the Actions dropdown
2. Push the data through MME
Go to the RD-Connect GPAP, enter the RD-Connect ID of your patient in the sample section and click in the MME icon. A form will appear pulling all the information you have already entered: clinical symptoms are extracted from PhenoTips and information concerning the genes is extracted from PhenoTips and the TAG functionality of the GPAP:
In the target endpoint section you will be able to select if you want to match your patient internally (within the RD-Connect database) or externally to the whole MME networks through PhenomeCentral.
You can also add additional HPOs or gene by typping directly in the form.
Once you have checked all the information, you can submit the data clicking in submit. The application will return the list of patients that matched your query ordered by MME score. MME score is defined from 0 to 1, being 1 a perfect match. This score is divided into two part 0.5 for the gene match and 0.5 for the phenotypic match.
If you have a positive match and you want to contact the corresponding data owner, click to Initiate contact and an email will be send to you and the corresponding submitter to initiate a possible collaboration.
8.2.2.Push to PhenomeCentral
If you do not have a PhenomeCentral account, go to https://www.phenomecentral.org/ and register.
Go to the RD-Connect PhenoTips instance, open the form of the case you want to submit to PhenomeCentral and select push to PhenomeCentral
Log in with your PhenomeCentral credencials and confirm that you have the different consents:
Then select the fields from your form you want to be exported. As matchmaking scores are based in phenotypic similarities and genematch, we strongly recommend to submit information concerning:
- Genotype information
- Clinical symptoms and physical findings
- Diagnosis (ORDO)
All this information will be pulled directly from the form.
You can now push your patient to PhenomeCentral. A PhenomeCentral identifier will be provided. If any match ocurre you will receive an email to the account provided during the PhenomeCentral registration. The RD-Connect PhenoTips instance will track and record all submissions.
The Global Alliance for Genomics and Health’s “beacon” application programming interface has been implemented, which enables querying of the presence or absence of single variants in the RD-Connect cohort. This beacon is connected to the Beacon Network which is a search engine across the world’s public beacons. It enables global discovery of genetic mutations, federated across a large and growing network of shared genetic datasets.
You can easily submit your variant of interest to the Beacon Network selecting GA4GH beacon at the chromosome position level from the results section of the RD-Connect GPAP .