Emedgene is an AI-based platform, incorporating machine learning throughout the analysis and interpretation workflow in order to deliver the fastest time from genomic data to decisions. We apply machine learning models that retrieve evidence-backed answers and provide exceptional decision support.

• Emedgene’s automated interpretation algorithms generate an accurate shortlist of up to 10 potential causative variants. In a joint study of 180 solved cases with Baylor Genetics, 96% of cases were successfully solved by the algorithm. See Meng et al, Genetics in Medicine, 2023 publication for more details.

• The platform is not a black box, and overlays a layer of explainable AI (XAI), presenting supporting evidence from the literature and databases which significantly reduces the time to interpret a case.

• The algorithms use a proprietary Emedgene knowledge graph which incorporates information extracted from literature with Natural Language Processing, as well as from public databases and is updated on a monthly basis.

• Dozens of additional algorithms are incorporated throughout the workflow.

Overall, the system combines AI in a highly optimized and customizable workbench, in order to automate the most time-intensive aspects of genomic analysis and research.

The Emedgene platform utilizes the Okta Identity Management solution to control user access. This improves user management, enhances access and authentication security, and allows organizations to implement single sign-on for their users.

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To streamline case review, the AI Shortlist pre-selects the list of variants likely to be causative for each case:

Most Likely Candidates

Variants that are most promising for solving the case. This list is limited to 10 top-scored variants but may include more if more than one variant is tagged per gene (suggesting compound heterozygosity). We can change the Most Likely Candidates number limit upon request.

Candidates

Several dozen highly scored variants worth considering.

As of version 30.0 and onwards, the ranking of variants by AI Shortlist considers both SNVs and CNVs, including SNV + CNV compound heterozygotes. Starting from version 32.0, AI Shortlist additionally considers SVs, mtDNA variants and STRs.

The AI Shortlist rates variants based on predicted variant effects, alternative allele frequency, familial segregation pattern, phenotypic match, in silico predictions, and other relevant information from scientific papers and databases.

During the case review, you can untag variants selected by the AI Shortlist or manually tag ones not selected by the AI Shortlist.

Click on the user initials or profile picture at the rightmost corner of the Top navigation panel to open the Settings dropdown menu. From there, you can enter:

My Settings

Add or edit your professional credentials, profile picture, contact information and organization's details, and review roles and permissions granted to you.

Management

Manage data storage, custom Case statuses, Case labels, create, edit and delete gene lists, set how long until a case becomes "stale", and assign user groups.

User Management

Add, activate and inactivate users and manage user roles.

Network

Create networks, establish data sharing policies for each network, delete and leave networks.

Organization Settings (33.0+)

Choose a software version for your organization, set up a case identifier, and select your preferred URLs (the latter - only for ILMN cloud users).

Help

Next to the user's initials or profile picture is a question mark Help icon. Clicking on this icon expands a dropdown menu with the following options:

• Support Chat: reach out to our Customer Support team anytime without leaving the page;

• What's New: check out the new features, enhancements, or any other updates related to the platform.

Whenever an organization is created, we automatically allocate bucket folders in AWS S3 cloud storage to it:

• Path for upload

<Region_Cloud>-emg-auto-samples/<org_name>/upload/

Folder intended to store input case files.

Authorized user has view and upload privileges.

• Path for download (32.0+)

<Region_Cloud>-emg-downloads/<org_name>/ 

This folder contains a partially annotated (excluding results of proprietary algorithms) VCF file per case.

Authorized user has view and download privileges.

• Path for DRAGEN output (32.0+)

<Region_Cloud>-emg-auto-results/<org_name>/ 

This folder contains DRAGEN output files.

Authorized user has view and download privileges.

To get access to your upload, download and DRAGEN output folders, you need to get a key pair consisting of an access key ID and a secret access key. Creating, deactivating, activating and deleting credentials is available for users with Manager and Manage S3 Credentials roles.

You can create and use up to two dynamic access keys at the same time.

When you require technical support, you have the option to generate a new key pair specifically for the troubleshooting process. After the issue has been resolved, you can delete the credentials to ensure security of your system.

The newly generated credentials will only be saved in AWS Identity and Access Management (IAM) and not in our database.

How to create a key pair

1. In Settings > Management > S3 Credentials, click on Create Access Key.

2. You can retrieve the secret access key only when you initially create the key pair. If you lose it, you have to create a new key pair. To immediately copy the secret access key to a secure location, use the Copy to clipboard button.

How to deactivate a key pair

In Settings > Management > S3 Credentials, click on Deactivate in the corresponding key pair card.

How to activate an inactive key pair

In Settings > Management > S3 Credentials, click on Activate in the corresponding key pair card.

How to delete a key pair

In Settings > Management > S3 Credentials, click on Delete in the corresponding key pair card. Only inactive key pairs can be deleted.

Scope

Bring Your Own Key (BYOK) is a security feature that allows clients to use their own encryption keys to protect their data. This ensures that clients maintain control over their encryption keys and, consequently, their data. Only Enterprise level support accounts can access this feature, and it requires assistance from Illumina support for setup.

Supported Key Management Services

Illumina supports integration with popular Key Management Services (KMS) such as Azure Key Vault and AWS KMS for managing your encryption keys. This integration allows clients to use their existing key management solutions for generating, storing, and managing their keys securely.

Azure Key Vault

Azure Key Vault is a cloud service that provides a secure way to store and manage sensitive information like API keys, passwords, and certificates. It offers robust features for key management, including key generation, storage, and lifecycle management.

AWS KMS

AWS Key Management Service (KMS) allows you to create and control encryption keys used to encrypt your data across a wide range of AWS services and applications. It provides centralized management of encryption keys and integrates seamlessly with other AWS services.

These integrations ensure robust key management capabilities and enhance the security of your data through a combination of Illumina's BYOK feature and your preferred KMS provider.

Risk of Losing a Key

Losing the encryption key means that all data encrypted with that key will be inaccessible. This can lead to permanent loss of access to crucial information. It is imperative that clients securely store and manage their keys to prevent such risks.

Setup

Azure Key Vault Setup

Emedgene’s API server will encrypt the client’s information before storing in Emedgene’s database and decrypt that information when needed (e.g. running the pipeline). The key vault is managed by the customer. The customer needs to provide the following information.

Please see below instructions on how to get or create it

Application Tokens:

• Client Id

• Client Secret

• Tenant Id

The key information:

• Key URL

Create a new Application

1. Navigate to App registration

2. Register a new application, click “Register”

3. When you created the app, please copy Application (client) ID and Directory (tenant) ID

4. Go to Certificates and secrets (in the left menu)

5. Press “New client secret” and provide the “Value”

Create a new Key

1. Press New Key (Create key vault)

2. Specify key vault name, region (ie. East US) and pricing tier

3. Click “Next” to Access Policies

4. Press “Add access policy” and set Key permissions:

   1. Key Management Operations: -

   2. Cryptographic Operations: Decrypt, Encrypt, Unwrap Key, Wrap Key

5. Then set Secret permissions:

   1. Secret Permission: Get

   2. Select principal: select the application you created before (in Create a new Application step)

6. Finish with “Review + create”

Find key details

1. Navigate to the newly created Key vault

2. Select keys on the left side, select the key

3. Select the current version and copy “Key Identifier” https://<key-vault-name>.vault.azure.net/keys/<key-name>/<key-version>\

AWS Key Management Service (KMS) Setup

Description is coming soon.

Architecture

Emedgene’s API server will encrypt the client’s information before storing in Emedgene’s database and decrypt that information when needed (e.g. running the pipeline). The key vault is managed by the client, and Emedgene will only be provided with access to encrypt/decrypt functions in that key vault. This guarantees that the clients controls access to the information.

Illustration of data flow when creating a case in Emedgene platform:

Illustration of data flow when reading a case data from Emedgene platform:

A preliminary step to this solution is having a key vault owned by the client, and a key that Emedgene is given access to.

The client will create an access policy in the key vault of type “Application” and provide the matching key and secret to Emedgene. The access policy must contain permissions to perform encrypt and decrypt actions.

In order for Emedgene to integrate with the key, depending on the key vault provider, the client needs to provide the following information:

• Client Id

• Client Secret

• Tenant Id

• Key vault name

• Key name

Searching Encrypted Fields

Since some of our platform search capabilities run directly on the DB, we can’t directly search any data that is encrypted. To overcome this, we will implement a hashing search functionality as follows.

• The case data will still be fully encrypted in the DB as it is today

• Specific fields we want to make “searchable” - as defined by the customer, we will save their hash value alongside the encrypted data.

• Hashing will be done using SHA-256, and will include a secure random generated salt of 32 characters, which will be added to the value.

• The salt is unique and will not be used anywhere else in the platform.

• When the user enters a string to search, we will hash that value using all the salt values, and search those hash values.

Illustration of data flow when searching in Emedgene platform:

Illustration of data flow when creating a case with searchable field in Emedgene platform:

Appendix

Client->Emedgene API: Add New Test Request 
note right of Emedgene API: Process Request 
Emedgene API->Key Vault: PHI 
note right of Key Vault: Encrypt 
Key Vault->Emedgene API: Encrypted PHI 
Emedgene API->Emedgene DB: Store Encrypted PHI

Client->Emedgene API: Get Test Request 
emedgene DB->Emedgene API: Encrypted PHI 
Emedgene API->Key Vault: Encrypted PHI 
note right of Key Vault: Decrypt 
Key Vault->Emedgene API: Decrypted PHI 
Emedgene API->Client: Decrypted PHI

Client->Emedgene API: Add New Test Request 
note right of Emedgene API: Process Request 
Emedgene API->Key Vault: PHI 
note right of Key Vault: Encrypt 
Key Vault->Emedgene API: Encrypted PHI 
Emedgene API-> Emedgene DB: Get Salt 
Emedgene API-> Emedgene API: Hash Value using Salt 
Emedgene API->Emedgene DB: Store Encrypted PHI + Hashed value

Client->Emedgene API: Search string 
Emedgene API->AWS Secrets: Get Salt 
Emedgene API-> Emedgene API: Hash string using Salt 
Emedgene API->Emedgene DB: Search hashed string 
Emedgene DB->Emedgene API: Search results 
Emedgene API->Client: Search results

\

General CSV format requirements

The following are the general format requirements for a CSV file used to create multiple cases:

1. The file must have a .csv extension.

2. The file must contain a [Data] header.

3. The row after [Data] header must include the field names identifying the data in each column. The column names are case-sensitive.

4. The row after the column name header and each subsequent row represents a sample.

5. Each column represents a data field.

6. It is essential that there are no empty rows between the [Data] header and the last sample row.

7. Number of cases per file can’t be greater than 50.

8. On versions before 34.0, cells should not contain commas. Consider replacing the commas with semicolons.

CSV schema

1. Mandatory fields

Must be present in the sample table at all times.

1. Case Type;

2. Family Id;

3. Phenotypes OR Phenotypes Id.

2. Conditionally mandatory fields

If these fields are left empty, it will result in the creation of an empty sample.

1. BioSample Name;

2. Files Names;

3. Storage Provider Id;

This field is mandatory if Files Names is empty:

1. Sample Type.

This field is required if the "auto" option is used for Files Names (only relevant for BSSH):

1. Default Project.

3. Optional fields

The sample table may include these supported optional columns.

1. Boost Genes;

2. Clinical Notes;

3. Date Of Birth;

4. Due Date;

5. Execute now;

6. Gender;

7. Gene List Id;

8. Kit Id;

9. Label Id;

10. Opt In;

11. Relation;

12. Selected Preset;

13. Visualization Files.

4. Custom fields

The sample table may contain custom columns to suit your specific needs and include any relevant information that is important for your workflow.

Custom field examples:

Batch case .csv file validation rules

*Required BSSH file path format:

For BSSH, it is necessary to use the actual names (numbers):

instead of aliases

The Quality Filters allow one to filter variants by variant quality metrics. The filter can operate in a Simple or Advanced mode.

Modes

Simple

Select a minimum degree of sequencing Quality (Low, Moderate, High).

Advanced

For SNVs and Indels:

• Select a minimum degree of sequencing Quality (Low, Moderate, High),

• Define minimum Mapping Quality (0-60 - value can be exceeded using the text box),

• Specify minimum Depth (0-500 - value can be exceeded using the text box),

• Set minimum number of alternate reads in Alternate Read (0-500 - value can be exceeded using the text box). Note: available for cases run with pipeline version 5.26+.

• Set limits on Allele bias (0-100). Note: when applied to mtDNA variants, the Allele bias filter operates on heteroplasmy levels.

For CNVs:

• Set limits on CNV Length (50bp, 1kb, 10kb, 100kb, 1Mb, 100Mb, Max CNV length),

• Set minimum CNV Bin Count (1, 5, 10, 25, 50, 100, 500).

Default values

• Quality: Moderate and High,

• Mapping Quality ≥45,

• Depth ≥ 10,

• Alternate Read - no filtering,

• Allele bias - no filtering,

• CNV Length - no filtering,

• CNV Bin Count - no filtering.

As of version 2.26:

The Top navigation panel of the platform serves as a guide to the platform. It contains:

• Dashboard, Cases and Add new case buttons lead to the corresponding pages

• Case search bar

• Settings dropdown menu activated by clicking on the user name or profile picture

• Help dropdown menu activated by clicking on the question mark icon

• Emedgene Applications menu activated by clicking on the app launcher icon on the left

As of version 2.26:

The Dashboard provides a glance at key performance indicators for an organization and depicts an overview of the user activity on the Emedgene platform.

This page is divided into two panels and contains the following subsections:

Lefthand panel

• Emedgene Knowledge Base panel reveals the total amount of known polymorphisms, pathogenic variants, and gene-disease connections considered during analysis. It also indicates the number of scholarly publications processed by Emedgene's novel textual recognition platform, backed by natural-language processing and artificial intelligence.

• Diagnostic Yield panel presents the proportion of "solved" cases out of the total number of the organization's cases of the same type.

• Status Diagram panel displays the total number of the organization's submitted cases as well as the numbers of cases under each status.

• Stale Cases panel highlights the cases that are stuck at one of the intermediate stages of the analysis, and are not finalized.

Righthand panel

• Network Activities: The right panel displays a timeline of activities performed by multiple users within the organization. This log includes activity like creating a case, verifying a Preset, changing a Case status, generating a report, etc.

The Emedgene platform is divided into two applications:

• Analyze - genomic analysis workbench,

• Curate - the knowledge management system.

To switch from Analyze to Curate:

Go to the nine-dot app launcher icon located on the left of the Top navigation panel and select Curate from the dropdown menu.

To switch from Curate to Analyze:

Go to the nine-dot app launcher icon located on the Curate navigation panel and select Analyze from the dropdown menu.

Welcome to Emedgene, where we unlock genomic insights for hereditary disease and streamline your tertiary analysis workflows.

So you've signed in and can't wait to get started? Here we will guide you through the platform architecture, case creation, and results review. You can dive a bit deeper by following the links and exploring manuals for the platform's applications:

• Analyze - Genomic analysis workbench, where you can accession, interpret, curate and report on your cases, while also efficiently managing the lab workflow.

• Curate - A repository for all of your organizational curated knowledge.

Look around

The platform is operated from the Top navigation panel.

By clicking on the corresponding buttons, you can enter:

• Cases page

• Add new case page

• Emedgene Applications menu

• Help dropdown menu

• Settings dropdown menu

Create a case

To enter the Add new case flow, click on the namesake button on the Top navigation panel. Here:

• Select file type,

• Upload files,

• Create a family tree,

• Annotate each sample with clinical information,

• Specify analysis details, and

• Launch the analysis!

You'll be notified when results are ready.

Examine the analysis results

Select a case to review on the Cases page. You'll be directed to the Individual case page that:

• Showcases an AI-curated shortlist of variants suggested to be checked first, namely Most Likely Candidates and Candidates,

• Provides numerous customizable filters to help you explore the total list of genetic variants by yourself, and

• Documents all the case-related information like Case status, sample quality metrics, and versions of all the resources used during case analysis.

On the Variant page, each variant can be thoroughly investigated and accordingly tagged.

When you're ready to finalize the case, indicate the end result of the analysis and variants to be reported in the Case interpretation widget.

Click on the question mark icon of the Top navigation panel to open the Help dropdown menu.

From there, you can access:

• Help Center. Feeling curious? Dive right in.

• What's New. Check out the release notes to be on top of our latest and greatest features!

Before you proceed to this article, make sure you understand data storage management basics.

Update Azure Blob Storage Credentials

In Settings > Management Tab, add or edit the required credentials: CLIENT_ID, CLIENT_SECRET, TENANT_ID, and ACCOUNT_URL.

See the table below to learn where to look for them in your Azure account.

Blob Integration Setup

Create an App registration

1. In Microsoft Entra ID, click on App registrations.

1. Select New registration.

2. Fill the name of the application & press "register."

3. You got to the registered app page: (CLIENT_ID / TENANT_ID) From this you can retrieve: Application ID and Tenant ID. Both are marked in the screenshot.

1. Press "Certificates & secrets"

2. Press on "New Client secret"

1. Fill the "Description" and change expires to 12 months. (or according to your organization policy), than press "Add"

8. Get the CLIENT_SECRET from this page.

1. Give this App registration roles and read access to the relevant Blob.

Azure Blob configuration

1. Go to Azure Storage accounts

1. Get into the relevant Storage account

1. Press on "containers"

1. Press on the relevant container

2. Press on "Properties"

3. Copy the ACCOUNT_URL\

For Internal support:

Errors for bad connections can be found in CloudWatch on particular FRY log stream

Search for: BlobApi, BlobFs, azure.

Emedgene users are defined by roles. Roles are managed in Settings > User Management. Access to the User Management tab is restricted to those with the appropriate permission.

The available roles for Emedgene are described below:

If you are not seeing part of the roles from the user management interface, please be in touch with our support.

Coming in V37.0: Google Cloud storage support

Google Cloud Storage Credentials update procedure

How to get the client credentials?

1. Go to the google cloud Console.

2. Navigate to IAM & Admin - In the left sidebar, go to IAM & Admin > Service Accounts.

1. Create a New Service Account: Click on the "Create Service Account" button at the top.\
2. Fill in the Service Account Details:

   • Service account name: Give your service account a name.

   • Service account ID: This will be automatically generated based on the name.

   • Description: Optionally, provide a description for the service account.

   Click "Create and Continue".

   example:\
3. Assign Roles to the Service Account:

   • In the Grant this service account access to project step, you’ll assign the necessary roles.

   • Grant these role:

     • "storage object viewer" (read-only access)

4. Create the Service Account:

   • After assigning the roles, click "Done".

5. Generate and Download a Key:

   • Find your newly created service account, click the three dots on the right, and select "Manage Keys".

   • Click Add Key > Create New Key and choose the JSON format.

   • Download the key and store it securely, as it is used for authentication in your code or applications.

6. Encode the key in base 64:

   • use python function: put this function and your json (here named json_file.json) in the same directory and run.\

     Copy

     import json
     import base64
     
     
     def encode_json_to_base64(json_file):
         # Read JSON data from file
         with open(json_file, 'r') as file:
             json_data = json.load(file)
     
         # Convert the JSON data to a string
         json_str = json.dumps(json_data)
     
         # Encode the string to bytes, then to Base64
         json_bytes = json_str.encode('utf-8')
         base64_bytes = base64.b64encode(json_bytes)
     
         # Convert Base64 bytes back to a string
         base64_str = base64_bytes.decode('utf-8')
         # Print the Base64-encoded string
         print(base64_str)
     
     
     encode_json_to_base64('json_file.json')

   • save the output printed.

Add the storage provider to Emedgene platform:

• Add the above 3 values into the appropriate fields:

  • Client_credentials_base64: pasting the output of 8.

  • Bucket: the bucket name.

  • Path: for default, fill with / else, put your path in the bucket. Seperate directories with /

CORS - Visualisation

1. Download and install the Google Cloud SDK from the Google Cloud SDK Install page. LINK

2. Select Your Platform (Windows, macOS, or Linux), download and run.

3. Initialize and Authenticate with Google Cloud: In the Cloud SDK Shell/terminal, run: gcloud init This will open a browser window to authenticate your Google account. Follow the instructions to log in and select your project.

4. Set CORS Configuration via gcloud: Create a JSON file (cors.json) on your machine with the CORS rules. Example\ it should look like:

   Copy

   [
       {
         "origin": ["https://<host_name>.emg.illumina.com"],
         "method": ["GET"],
         "responseHeader": ["emgauthorization"],
         "maxAgeSeconds": 3600
       }
   ]

notice:

• origin: if using Illumina cloud:

  https://host_name.emg.illumina.com

  else, Emedgene cloud:

  https://host_name.emedgene.com

1. Apply CORS Configuration to Your Bucket: run the next command. gcloud storage buckets update gs://your-bucket-name --cors-file=cors.json

2. Verify the CORS Configuration: gcloud storage buckets describe gs://your-bucket-name

How to open a case

To open a case, mouse over the corresponding row in the Cases table and click on the Open case text next to the Case ID (first column). Alternatively, once a row is selected, clicking on it again will open the case as well.

How to filter cases

Go to Filters, select the field under Field, then choose or manually input value under List and click on Apply. To add another filter, click on Add new.

To remove a filter, under Active filters, click on the cross icon on the right of the filter setting. To clear filters altogether, click on the cross icon on the right of Filters.

Available filters include:

• Case Id

• Status: Issue reported, Uploading, In progress, Reanalysis, Archived, Delivered, Confirmed, Approved, Pending Sequencing, or any other customized case status

• Participants - users involved in the case submission, analysis, finalizing, or those who subscribed to receive updates on the case.

• Type: Custom Panel, Exome, Whole Genome

• Sample Id

• Resolved: Resolved, Not Resolved

• Label: any customized Case label

How to sort cases

You can sort cases by:

• Creation date, or

• Due Date.

To do this, hover over the column name and click on the up or down arrow to sort ascending or descending, respectively. The current sorting order is depicted as a single up or down arrow symbol next to the column's name.

Alternatively, you can click on the name of the column and select Sort ascending or Sort descending in the dropdown menu.

How to search for cases

You can use the Case search tab in the top bar to search for cases by the Case ID or Proband ID.

How to group cases

To group cases by Case Status, go to Group and select Status; to undo grouping, select None.

How to tweak Cases table view

1. Select fields to be displayed

2. Change column order

3. Change column width

Select fields to be displayed

A. Select fields to be displayed: go to Fields and set a toggle switch next to each field name in on or off position per your desired view.

B. Hide the currently displayed field: click on its title and select from the dropdown menu Hide column.

Change column order

A. Drag and drop columns: hover over the column title cell, click on the six-dot icon on the left to the text, drag to the desired location and drop.

B. Set column order under Fields: go to Fields, hover over the field name, click on the six-dot icon on the left to the text, drag to the desired location and drop.

C. Move a particular column: click on the column title and select from the dropdown menu Move left or Move right.

Change column width

Grab the right or left border of the column title cell and drag it with your cursor to the desired width.

​ ​

To directly import files from your storage, link storage to your organization in Emedgene.

How to create a link between storage and organization:

1. Click on the user initials or profile picture at the rightmost corner of the Top navigation panel to open the Settings dropdown menu. Select Settings.

1. Select the Management tab. Under Storage is a list of currently linked storages. To add a new one press on Add Storage button.

1. Choose a Storage Type from:

   1. Azure Data Lake;

   2. Azure Blob;

   3. AWS S3;

   4. File Transport Protocol (FTP);

   5. Secure File Transport Protocol (SFTP);

   6. Illumina Basespace (BSSH);

   7. Illumina Connected Analytics (ICA).

1. Fill in the required credentials.

2. Click on Add storage:

1. Check the connection to confirm that the storage is successfully linked.

To do this, find the storage in the Storage List and check the cloud icon next to its name: 1. If it's green, the connection is set correctly; 2. If it's red and strikethrough, something went wrong. Hover over the icon to see details.

How to edit storage information:

In the Storage List press Manage on the right to the storage details.

How to remove a link to storage:

In the Storage List press Delete on the right to the storage details.

Add new case page > Select sample type screen.

You can select the sample's file type from the given options:

1. FASTQ: .fastq.gz, .fq.gz, .bam, .cram.

2. Project VCF: .pvcf, .vcf, .vcf.gz, .pvcf.gz

3. VCF: .vcf, .vcf.gz.

This section will guide you through adding new cases to the Emedgene platform.

Please follow the steps as described below:

1. Click on the Add new case button on the Top navigation panel.

2. At the Select sample type page, select the file type for your case analysis. Click Next to proceed to the Family tree panel.

3. The page is divided into two panels: Create family tree (left) and Add patient information (right).

1. In the Create family tree panel (left):

   • Build a pedigree using the visual tool;

   • Add Clinical Notes (optional) in a free text panel. In this section, you can record additional clinical information that does not fall under the other categories or provide further details that can give context and help solve the case.

   • You have an option to upload a file that includes description of the clinical presentation (.pdf, .xls, .txt, .doc, .jpeg, .jpg formats are supported). HPO terms for Phenotypes and Diseases are extracted from the files and can be added to Proband's Phenotypes in Patient info section.

   • You may select suspected Inheritance mode(s). This is for the case record and won't be used during analysis.

   • Select whether you want Secondary findings in Proband to appear in the AI Shortlist analysis results (checkbox).

1. In the Add patient information panel (right) for each of the family members:

   • Add a sample;

   • Fill in a sample name (for cases starting from VCF, this must correspond to the corresponding proband or family member header within the file);

   • Fill in the required patient details;

   • Click Next to proceed to the Case info screen.

1. In the Case info screen:

   • Select case type (Custom Panel, Exome, Whole Genome, or other). When running cases as Exome, variants outside exons ±50 bp are filtered out and won't appear in the results.

   • Pick whether you want Carrier Analysis to be carried out (checkbox). Carrier analysis requires you to provide us with a targeted genes list.

   • Sequencing Information (Choose from existing kit, No kit). You can indicate if there was an Enrichment Kit used if you wish to compare the breadth and depth of coverage to that expected for the kit used. RefSeq coding regions will be used as a reference if no kit is provided. This option is relevant for Custom Panel and Exome case types. In the Kit info section, fill in the Enrichment Kit and optionally Lab, Machine, Sequencing reagents, and Expected coverage.

   • Select genes list (All genes, Phenotype based genes, Existing gene list, Create a new gene list) - indicate if you want the analysis to be limited to a specified list of genes.

   • Select preset group: We can implement different combinations of Presets to be used for different case types (i.e. Presets for exome may be different from Presets for genome) as defined by your SOPs to further streamline case review.

     🆕 34.0+: If the user does not select a Preset group, the system automatically assigns the default Preset group to the case. The default Preset group is indicated by the word "default" in parentheses after its name.

   • Confirm subject consent for extended sharing (32.0+).

   • Optional: Additional case info:

     • Indication for testing. Add free-text notes.

     • Label. Add labels to your case. You can choose among the labels created beforehand by your organization's manager. Labels cannot be added after case creation.

   • Summary: confirm the selected case type and genes list before completing case creation.

   • Click Next to complete case creation.

1. In the Done screen:

   • The Case ID is displayed;

   • Add participants to your case - subscribe your colleagues to notifications on Case status change.

Log in to Emedgene and navigate to Settings in the upper right-hand corner of the page.

Click on the Management tab and then on Add Storage.

Choose Illumina BaseSpace storage type.

Fill Client Key, Client Secret and App Token as provided from BaseSpace (a description on how to get this information is provided below) and click Add storage to complete the setup.

• Via Command Line

• Via BaseSpace Developer Portal

Via Command Line

Prerequisite

Install BaseSpace CLI (Command Line Interface)

# Linux
$ wget "https://launch.basespace.illumina.com/CLI/latest/amd64-linux/bs" -O $HOME/bin/bs
# Mac
$ wget "https://launch.basespace.illumina.com/CLI/latest/amd64-osx/bs" -O $HOME/bin/bs
# or
$ brew tap basespace/basespace && brew install bs-cli
# Windows
$ wget "https://launch.basespace.illumina.com/CLI/latest/amd64-windows/bs.exe" -O bs.exe

Follow the instructions on the BaseSpace CLI Installation Page if needed.

Authenticate

On BSSH, login to the workgroup you want to connect as the storage.

Once the BaseSpace CLI is installed, run the authentication command in the terminal.

$ bs auth

The command will direct you to a link which requires to login.

After the authentication was completed successfully, find the access token in the config file.

$ cat .basespace/default.cfg

The result should look like -

apiServer   = https://api.basespace.illumina.com
accessToken = 

Populate the App_token with the accessToken value, and Server with the apiServer URL from the BSSH config file.

Client_key will be displayed in subsequent menus, so a descriptive name such as the workgroup name can be used.

Client_secret is unused when the App_token is available and can be set to "x".

Via BaseSpace Developer Portal

Go to the BaseSpace developer portal and login.

Go to My Apps and click Create a new Application.

Fill details for the application and click on create an application.

Fill details and press save.

Go to My Apps and click on your new app. Then go to the credentials tab.

You will find the Client ID (Client Key), Client Secret and App Token to enter to Emedgene platform.

Add new case page > Family tree screen > Add patient information panel > Add sample section

You can choose one of the following options:

1. Existing sample - pick one of the samples already loaded on the platform

2. Upload New Sample - upload files from your PC and enter sample name

3. Choose from storage - choose files from your cloud storage and enter sample name

4. No sample - postpone uploading files but proceed with case creation or skip uploading files for family members other than Proband

Add new case page > Family tree screen > Add patient information panel > Patient info section

1. Fill in the boxes:

1. Sex (33.0+) / Gender (≤32.0) (*)

Options: Male, Female, Unknown.

2. Relationship

The default fixed value for Proband is Test Subject.

3. Date of Birth

Expected format: mm/dd/yyyy.

4. Medical Condition (*)

Options: Affected, Healthy.

The default value for Proband is Affected, but you may change it to Healthy.

5. Proband Phenotypes (*)

To add all relevant phenotypes for the Proband, use one of the following methods:

1. One by one (Selection mode),

2. In a batch (Batch mode),

3. Extract HPO terms from the file uploaded in the Clinical Notes section, or

4. Automatically infer disease-associated phenotypes (see Proband Suspected Disease Condition below).

Selection mode

Please follow the steps described below for each phenotype:

1. Enter an HPO term (e.g., Hypoplasia of the ulna), an HPO ID (e.g., HP:0003022), or a descriptive phenotype name (e.g., Underdeveloped ulna) in the search box.

2. Select a matching term from a dropdown menu and press Complete after you've added all the terms and additional patient information below.

Batch mode

Paste a list of comma-separated HPO terms or HPO IDs (🆕32.0+) in the search box and press Complete.

Extract HPO terms from the file uploaded in the Clinical Notes section

In the Clinical Notes section upload a description of the clinical presentation in .pdf, .xls, .txt, .doc, .jpeg, or .jpg format. Among the extracted HPO terms for Phenotypes and Diseases select the ones you want to add to Proband's Phenotypes.

6. Proband Suspected Disease Condition.

Enter the disease name in the search box, select a matching term from a dropdown menu and press Complete. All the associated phenotypes will be automatically added to the Proband Phenotypes. To remove any phenotype described for the disease but not observed in your patient, click the ☒ button next to the HPO term in the Proband Phenotypes list.

7. Suspected Disease Penetrance

Enter the suspected disease penetrance as a percentage.

8. Suspected Disease Severity

Select the appropriate category to indicate the severity of the disease symptoms observed in the patient: Mild, Moderate, Severe, Profound.

9. Consanguinity

Mark the checkbox if applicable.

10. Patient Ethnicities

Paternal and Maternal. Enter the ethnicity name in the search box and select a matching term from a dropdown menu.

2. ​Click on Complete once all the information is added.

However, if you have an Enterprise account and you would like Emedgene managed DRAGEN solution to save the DRAGEN output files in your own bucket, reach out to techsupport@illumina.com and follow this steps:

Emedgene visualizes data in IGV directly from your AWS S3 bucket. In order to do it, you should enable CORS for the Emedgene application URLs.

This feature is only related to saving Dragen output files in your own bucket when using Dragen through Emedgene (without ICA).

If you are looking to:

• Import data from AWS S3 to Emedgene go to Manage data storages

• Integrating any data storage to Emedgene go to Manage data storages

• Download any data from Emedgene go to Manage S3 credentials

Bring Your Own Bucket

Bring Your Own Bucket, also known as BYOK, enables you to control your DRAGEN file outputs.

Emedgene managed DRAGEN solution saves the DRAGEN output files in a detected AWS S3 bucket that you have access to using your S3 credentials.

However, if you have an Enterprise account and you would like Emedgene managed dragen solution to save the DRAGEN output files in your own bucket, reach out to techsupport@illumina.com and follow this steps:

1. Create an AWS bucket

Emedgene requires access to the root folder, which means a dedicated bucket might be appropriated.

2. Edit Bucket policy

Bucket policy should allow Emedgene user access to the bucket.

Example bucket policy:

{
    Coming Soon
}

3. Allow illumina.com and emedgene.com for CORS

Emedgene visualizes data in IGV directly from your AWS S3 bucket. In order to do it, you should enable CORS for the emedgene application URLs.

Example CORS policy:

{
    Coming Soon
}

4. Test and validate the configuration with Illumina support

We will require to run a case and validate the managed DRAGEN pipeline finish successfully and all features are available in the platform.

Managing AWS S3 Lifecycle policy

If a customer enables an AWS S3 Lifecycle policy in order to archive or change the S3 tiers for different files, they might create an adverse effect on the platform.

Emedgene provides the tightest integration with DRAGEN for germline variation analysis, providing accuracy, comprehensiveness, and efficiency, spanning variant calling through interpretation and report generation.

Compatibility with DRAGEN Variant Callers

Extensive Compatibility with Additional Variant Callers

The Emedgene platform supports a variety of variant callers and applies specific quality parameters for each. The quality assessment is an essential step in the Emedgene pipeline because variants with low quality will not be considered by the AI components.

If the variant caller is not supported or not recognized, a default quality function will be applied. The default parameters are built on GT (genotype), depth (DP) and allele bias (AB). These fields are mandatory, and their absence will induce “Low quality” for all variants.

The following variant callers are currently supported on the Emedgene pipeline, providing a header with the variant caller command line should be present within the VCF headers.

Additional callers can be supported on demand.

> Family tree screen > Create family tree panel

Build a pedigree via the visual tool.

It is ideal that a proband selected for case analysis is affected and has disease phenotype(s).

You can add a Father, a Mother, a Sibling, or a Child to any family member, starting with the Proband. To do this, choose their icon, then click on the Add family member button in the bottom right corner of the pedigree builder to select a family member.

To delete a family member, choose their icon, then click on the Delete Subject button in the top right corner of the Add patient information panel.

> Case info screen > Select genes list

Select gene list

You can limit analysis to a gene list in the platform while creating a case. Choose between:

1. All genes

No limitation of the analysis.

2. Phenotype based genes

The list is automatically built from genes related to the HPO terms you entered for the case (per Emedgene knowledge base).

3. Existing gene list

Select one of the previously added gene lists from a dropdown list.

4. Create a new gene list

Generate a new virtual panel: add a List title and then add all the gene symbols one by one () or in a batch ().

Selection mode

For each gene please follow the steps described below: Enter a gene symbol in the search box in the right panel (Candidate Genes) and select a matching symbol from a dropdown menu.

Batch mode

After selecting batch mode, paste a list of comma-separated gene symbols in the search box in the right panel (Candidate Genes).

Gene list modes

You can choose between two different modes of a gene list feature:

1. Gene panel mode

The default option.

Analysis is limited to the selected gene panel, no variants in other genes are considered in the results. If this in silico panel is used for analysis of exome or genome data, the gene restriction may be lifted during manual analysis to "open-up" the entire exome or genome for analysis.

2. Boost genes mode

Enabled through checkbox.

Analysis is performed for variants in all the genes. Variants in the targeted genes get upgraded scores during prioritization by the AI Shortlist algorithm.

How to filter variants by a gene list

1. Candidate Genes filter

2. Gene Lists filter created in a case

3. Gene Lists filter created in Settings

First, fill in the List title and click Add button. Then add the gene symbols one by one (Selection mode) or in a batch (Batch mode).

• Selection mode - for each gene please follow the steps described below: Enter a gene symbol in the search box (Candidate Genes) and select a matching symbol from a dropdown menu.

• Batch mode: Paste a list of comma-separated gene symbols in the search box (Candidate Genes).

When you finished, press Save.

To view the Gene list in read-only mode, click on its name. By pressing the corresponding icons next to the Gene list's name, you can duplicate, edit or delete it. If a gene list has already been used by a case in the platform, you will only have the possibility to duplicate it.

Cases table lists all the genomic sequencing cases submitted by your organization. It is the primary component on the left-hand side of the Cases tab.

Brief column description:

Case ID

A unique ID assigned to a case by Emedgene.

Proband ID

Proband's sample ID submitted by creating the case in the platform.

Status

Creation Date

Automatically saved.

Due Date

Can be set, changed or removed on the spot. To set a date, click on the calendar icon and select a date of interest. To change it, click on the previously set due date and select a new one. To remove the due date, click on the cross button next to it.

Phenotypes

Proband phenotypes as submitted by the user.

Participants

Users involved in the case submission, analysis, finalizing, or those who subscribed to receive updates on the case. To receive email notifications on your colleagues' activities in the particular case, click on Subscribe icon. To unsubscribe, hover over your initials and click on the cross button.

Type

Case Type (Custom Panel, Exome, Whole Genome).

Label

Dedicated user groups

> Family tree screen > Create family tree panel > Show Secondary Findings

While creating a case, you can choose if you want Secondary (Incidental) findings in the Proband to appear in the results.

These are known or expected pathogenic variants in the genes that are unrelated to the primary purpose of the testing. The secondary finding genes list includes:

> Family tree screen > Add patient information panel > Patient info section

1. Fill in the boxes:

1. Sex (33.0+) / Gender (≤32.0) (*)

Options: Male, Female, Unknown.

2. Relationship

Indicates the family relationship of a subject to the Proband automatically inferred from the pedigree. Options: Father, Mother, Sibling, Child, Other.

3. Date of Birth

Expected format: mm/dd/yyyy.

4. Ignore Sample

Mark the checkbox if you want to exclude the sample from the AI Shortlist analysis and Inheritance filters while preserving genotype data.

5. Add Proband's phenotypes

If a sample shares some phenotypes with the Proband, you can copy them by checking this box. Proband's phenotypes will appear in a newly created Related Phenotypes section. To remove any of the proband's phenotypes not observed in a current individual, click the ☒ button next to the HPO term in the Related Phenotypes section.

6. Unrelated Phenotypes

Selection mode

Please follow the steps described below for each phenotype:

• Enter an HPO term (e.g., Hypoplasia of the ulna), an HPO ID (e.g., HP:0003022), or a descriptive phenotype name (e.g., Underdeveloped ulna) in the search box;

• Select a matching term from a dropdown menu and press Complete after you've added all the terms.

Batch mode

Paste a list of comma-separated HPO terms or HPO IDs (🆕 32.0+) in the search box and press Complete.

2. Click on Complete once all the information is added.

Case status indicates the current stage of case processing by the Emedgene platform or a genomic analyst.

Where can I find the current status of the case?

1. Status column of the ;

Built-in statuses include:

1. Uploading

The sequencing file is being uploaded on the platform.

Note: The Uploading status cannot be manually altered.

2. In Progress

Case is running.

Note: The In Progress status cannot be manually altered.

3. Delivered

The running stage completed, and the case is now available for users for analysis and review.

4. Finalized

Analysis and review completed.

Status Finalized by design should be assigned manually after summarizing the analysis findings through the Case Interpretation widget. Specifically, when finalizing a case, you should indicate its end result:

• Confidently Solved (Positive),

• Likely Solved (Positive),

• Further Investigation (Uncertain), or

• Unsolved (Negative).

Confidently Solved, Likely Solved and Further Investigation end result categories correspond to the Resolved case status supercategory, and Unsolved obviously falls into Not resolved (together with all the non-finalized cases). The indicated case analysis outcomes are used to calculate the diagnostic yield.

5. Archived

Indicates that the case is not subject to further review. Changing Case status to Archived requires technical support (pre-34.0 flow).

6. Move to trash 🆕 34.0+

Makes the case unaccessible. This status is only assigned manually.

7. Pending Sequencing

The case has been created, but is not connected to any genetic data.

8. Issue Reported

The case failed to run. Please check the integrity of the files used and verify that the variant caller is on our accepted variant caller list.

9. Reanalysis

The system is re-running the AI Shortlist algorithm for the case.

How to change the Case status

1. In the Individual case page Top bar, click on a dropdown icon next to the current case status.

2. Select the status from the menu.

1. In the Cases table, click on the current case status.

2. Select the relevant status from the dropdown menu.

Where can I manage Case statuses?

Version 33.0+:

With version 33.0 and later, you have the flexibility to manage Case labels at any time: create, add, or remove them directly in the .

Versions older than 33.0:

Once a case is created, Case labels cannot be removed or added.

If you're comfortable with scripting and API usage, you can upload multiple cases at once using those methods. But if you're not a technical expert, don't worry. There is a user-friendly alternative available in versions 32.0 or newer - importing a CSV file directly through the user interface.

Please follow the steps as described below.

1. Prepare a CSV file

CSV (Comma-Separated Values) is a simple file format used to store data in tabular form. A row represents a sample, and a column represents a data field.

Start by downloading a CSV template with an example line and mandatory and non-mandatory fields from the Add new case page set to Batch mode (see ). Fill the file with your data according to .

2. Upload a CSV file

1. Click on the + New case button on the .

2. Click on the Switch to batch button in the top right corner. You'll be directed to the Select file page of the Batch upload flow. Note: Here you can download a CSV template in the valid format.

3. Drag and drop a CSV file into the box or upload it from the file explorer. Wait for file upload and validation to finish.

3. Review file validation results

After validation is complete, you will be directed to the Batch validation page. It features validation results details for you to review:

• File name,

• Number of rows in the file,

• Number of cases to be created

• Number of errors found,

• Status message:

  • if no errors were detected, a success message will be displayed;

  • If any errors were detected, an error message will be displayed. You will be given the option to download a file with error details to help you diagnose and correct any issues with the data. Once you've corrected the CSV file, reupload it.

4. Create cases

1. Click on Create. A progress bar will appear on the right as the cases are created (Cases creation page).

2. If the cases have been created successfully, the Cases summary page will display the total number of cases that were created.

3. If there were any errors during the batch case creation process, the Cases summary page will display a table indicating the number of cases that were successfully created and the number of cases that failed.

You will have the option to download a CSV file containing two additional columns: Errors and Case ID. The Errors column will contain error messages for samples where case creation failed, while the Case ID column will contain the Case ID of a successfully created case for the lines where case creation was successful.

While adding a new case, you will build a pedigree and annotate each of the samples with data required for analysis ( > Family tree screen).

After the case has been created, the family tree is available in the panel (righthand panel of the Cases page).

Family tree legend:

1. Icon fill color in other pedigree members indicates the presence or absence of the proband's phenotypes in a present sample (regardless of the potential presence of additional unrelated phenotypes):

   • Filled - the individual is affected by all of the proband's phenotypes;

   • Half-filled - the individual is affected by some of the proband's phenotypes;

   • Empty - the individual is not affected by any of the proband's phenotypes.

2. Icon color intensity denotes whether sample files have been uploaded for the particular individual:

   • Full color - the sample has files loaded in the case;

   • Faded color - no sample files are available.

3. Icon line type indicates whether the sample is considered or excluded during analysis (relevant to samples with uploaded files only):

   • Solid - the sample is included in the analysis;

   • Dashed - the sample is ignored by Inheritance filters and the AI Shortlist algorithm, but you still can explore its genotypes. ​

​

Ethnicities of the proband's mother and father can be specified during the UI case creation. Starting from version 32.0.0, this can also be accomplished via API case creation. Please refer to the following list of supported ethnicities.

The Cases tab provides a bird's-eye view of all the previously submitted genomic sequencing cases.

The Cases tab includes:

• window that pops up on the right when activated

• on top

The Analysis tools tab contains multiple tools that facilitate a case review:

• - includes numerous adjustable Filters and Presets (on the left)

• - a user-customizable display of all the analysis results (core section)

• - when selecting a variant, the variant page opens, revealing a detailed annotation and other assessment tools for the particular variant.

The Top bar in the Individual case page indicates the Case ID and current .

Options available through the Top bar:

• Change the

• Reanalyze the case

• and write interpretation notes

• Preview the

Prerequisites

• Emedgene platform version >= 32

• Download and install node js platform via Minimum version required: 16 Upgrade existing installation: nvm install --lts

Batch upload via CLI (Command Line Interface)

1. Download the batch case create script. Replace my-domain with your Emedgene domain. Illumina cloud: my-domain.emg.illumina.com Legacy Emedgene cloud: my-domain.emedgene.com

1. Download the CSV template file.

1. Edit the downloaded batchCases.csv file. See for more details.

2. Execute the batch cases creator as java script using the command below. Replace my-domain with your Emedgene domain and my-email with your user email. A prompt for your Emedgene password will appear, enter the password and press Enter.

1. In case of validation errors in the input CSV, an output CSV called batchCases_results.csv will be created in the same location with detailed error results.

2. -l will create a log file in the same location.

More information can be found by running

Variant table columns:

To do this, click on the Export icon on top of the .

You can search for variants in the Variant search box by:

Single phenotype

"phenotype1" (e.g., "Mandibular prognathia")

Disease

"disease1" (e.g., Kabuki syndrome 1)

Disease inheritance mode

"inheritance mode1" (e.g., Autosomal dominant);

Genomic position

"coordinate1" (e.g., chr11:2686616)

Specific SNV/indel variant (32.0+)

"variant" (e.g., chr1:27089776G>T)

Genomic range

"range1" (e.g., chr11:2686616-2886620)

CNV length

"cnv_size:size1" (e.g., cnv_size:100000-10000000)

Gene symbol

"gene1" (e.g., BRCA1)

Multiple gene symbols added in batch

"gene1, gene2, gene3" (e.g., BRCA1, BRCA2, UBE3A)

Most of the above-listed options may be combined.

Presets are combinations of that match your case analysis SOPs.

For versions prior to 34.0, technical support is required to implement a customized filter Preset. But with version 34.0 and later, users can easily do it on their own.

Create filter Presets from active filters (34.0+)

To save Presets from active filters:

1. Open the panel and navigate to the tab;

2. Click on the three-dot icon;

3. Select Save as preset;

4. Enter a name for the Preset (Note: Avoid using non-Latin symbols that don't follow the ISO-5589-1 standard);

5. Click Save.

Where can I manage Presets? (34.0+)

1. In Presets, scroll down and click Add beside Gene Lists.

1. Select the gene lists you want to utilize as filter presets by marking the relevant checkboxes. Starting from version 30.0+, a search bar simplifies list navigation by allowing you to search by list name.

1. Click Save.

Presets originating from gene lists will appear in Presets under Gene Lists.

Review logic behind the Preset (32.0+)

On 32.0+, for a quick refresher, you may review the logic behind each Preset directly within your analysis flow. To do so, click on an downward arrow icon left to the Preset's name.

When you:

• Complement NGS with other genetic tests done on the side (long-read sequencing, optical mapping, CGH, SNP array, karyotyping/FISH, repeat-primed PCR, MLPA, Southern blot, etc), or

• Choose to report a few adjacent variants as a single multi-nucleotide variant,

the need to add variants on top of the analysis results arises.

You can manually add variants absent from the VCF or not called from the FASTQ. Supported variant types are SNV, CNV, UPD, ROH, and STR. SV is coming soon!

To manually add a variant:

1. In the Manually Add Variant window select variant type among SNV, CNV, UPD, ROH, and STR.

2. Fill in variant details according to the selected variant type:

1. Click on Create Variant.

Manually added variant's Variant page

To filter by manually added variants:

You can enter a specific case from the by clicking Full details in the corresponding row of the case table.

The Individual case page includes:

Displays a Case ID and and includes Case interpretation, Edit case info, and Report preview buttons.

Highlights a shortlist of variants, suggested to be reviewed first - Most Likely Candidates and Candidates.

Illustrates quality metrics for the sequenced samples.

Provides numerous customizable filters to help you explore the total list of genetic variants in compliance with your organization's standard case review process. You can export shortlisted variants in .xlsx format.

Documents versions of all the resources used during case analysis.