The Matchmaker Exchange05/07/17
The Matchmaker Exchange (MME) connects researchers and clinicians to identify novel Mendelian disease genes
The MME (www.matchmakerexchange.org) was initiated in October 2013 as a community-organised effort to connect clinicians and researchers with rare cases. Matchmakers had evolved in several national and international efforts to identify new Mendelian disease genes, such as FORGE and Care4Rare Canada which developed PhenomeCentral (phenomecentral.org), the Centers for Mendelian Genomics (National Human Genome Institute) which developed GeneMatcher (genematcher.org) in the US and the DECIPHER project in the UK (https://decipher.sanger.ac.uk/).
The goal of the MME was to develop a connection (application programming interface; API) that would allow exchange of information across these and other matchmakers so that cases would not have to be deposited in multiple databases. This API was launched as a federated system in July 2015. A special issue of Human Mutation in October 2015 described the MME, its API, connected matchmakers, and a few examples of successful disease gene discovery. The MME has become a demonstration project of both the Global Alliance for Genomics and Health (GA4GH, genomicsandhealth.org) and the International Rare Disease Research Consortium (IRDiRC.org).
It is easy to submit cases to a matchmaker, and guidance regarding which matchmaker to use is available at http://www.matchmakerexchange.org/i_am_a_clinician_laboratory.html. There is also extensive guidance about joining as an entire database on the MME website. There are monthly calls of MME participants as well as monthly calls of the technical group; both are open to all. The MME is governed by a steering committee (SC) comprised of one representative from each connected matchmaker and a representative from the GA4GH and IRDiRC. Most decisions are made on the monthly calls of all MME participants, but if necessary between calls or in cases of disagreement, the SC votes. The MME has periodic in-person working meetings to advance the platform in support of rare disease gene discovery. In addition, there is a meeting as part of the annual GA4GH meeting to align the MME with other genomic data-sharing initiatives.
Only cases submitted by researchers and/or clinicians can be exchanged over the MME. Patient-initiated connections are feasible within MyGene2 and GeneMatcher, but are not yet permissible over the MME. The API requires that the submitter be registered in one node, a submission ID, and candidate gene information (such as an Entrez or Ensembl Gene ID); optional additional information includes disorder number (OMIM or Orphanet ID), and phenotypic features exchanged as Human Phenotype Ontology (HPO) IDs (although GeneMatcher will also accept PhenoDB IDs and ICHPT IDs).
There is an end-user agreement required of any user of the MME:
- To make no attempt to identify individual patients in any MME database;
- To enable all cases submitted for querying to be stored in the query-initiating database for future matching;
- To obtain permission from the source of the matching data before publishing or presenting the results of queries, and to respect the privacy of patients in any publications and presentations;
- To acknowledge the MME, and the specific MME services that supported any discoveries in publications, as appropriate. See http://www.matchmakerexchange.org/citing;
- To acknowledge that all activities and requests for matches will be logged. Logging information will include full name, email address, time stamp of activity, query data, and the response; and
- To acknowledge that logging information will be available to the originating and the queried databases but it will not be shared outside MME. Logging information will not be used to gain knowledge of a user’s research activities for competitive purposes. It will be used to monitor MME services and to generate aggregate statistics to report on performance (e.g. at public events such as conferences).
Matchmakers are required to log and track queries and authenticate submitters. To become a bona fide member of the MME any new matchmaker must establish connections to at least two other matchmakers.
Two-tier consent requirements
Submissions involving only candidate genes and HPO terms do not require explicit informed consent, as this can be considered an extension of clinical care to establish a diagnosis. Submissions from a research context or including detailed phenotypic descriptions or multiple variants that could allow identification require informed consent. The onus for obtaining and assuring consent rests with the submitter. A detailed description of the consent structure is available at www.matchmakerexchange.org under the tab for resources.
GeneMatcher (genematcher.org) was developed by the Baylor-Hopkins Center for Mendelian Genomics to enable connections among researchers and clinicians with an interest in the same gene. It has been expanded to include patient-deposited cases as well as phenotypes and disorders, although a candidate gene is necessary for matching. GeneMatcher accepts submissions directly from any instance of PhenoDB, as well as direct submissions. Currently containing over 12,700 submissions from 3,310 users and enabling >10,000 matches involving >1,000 genes across the MME, GeneMatcher has already led to over 30 publications as well as the first publication of a match across the MME with Phenome Central.
PhenomeCentral (phenomecentral.org) was developed by the Hospital for Sick Children and University of Toronto. PhenomeCentral uses an interface based on the PhenoTips program and allows for granular consent-based controls of fields entered for any patient, including phenotypes, lists of candidate genes, or a whole exome VCF file. Users are also able to share data directly from their local PhenoTips implementation. PhenomeCentral has over 2,500 phenotyped cases from 952 users, and has enabled over 1,100 matches across the Matchmaker Exchange. PhenomeCentral is the matchmaker used by the Care4Rare Canada project, Undiagnosed Disease Network in the US, and Undiagnosed Disease Networks International.
DECIPHER (decipher.sanger.ac.uk) is the oldest and largest matchmaker with over 23,000 open access patient records and more than 12 years’ experience. All data available for query through the MME is open access and requests for connection go through a database administrator. DECIPHER includes single-nucleotide variants, copy number variants, and HPO annotations for submitted cases.
MyGene2 (mygene2.org) has been accepting patient-initiated case-level data deposition since April 2016 and currently contains 1,079 family profiles that are completely open access. It has been connected to the MME since summer 2016. Only cases attached to a clinician or researcher that include candidate novel Mendelian disease genes can be submitted for querying across the MME.
Broad matchbox was developed by the Broad Center for Mendelian Genomics. Its purpose is to function as a bridge to the Matchmaker Exchange from seqr, a genomic discovery platform developed by the MacArthur Laboratory. It is also available as open-source software under a BSD License to enable other databases to easily connect to the MME.
The Australian Genomics Health Alliance (AGHA) Patient Archive (mme.australiangenomics.org.au) is the node most recently connected to the MME. It includes unsolved cases that have undergone exome or genome sequencing as part of the Australian national effort.
Monarch Initiative (monarchinitiative.org) enables identification of animal models for human diseases based upon features. Phenotypes in human patients and animal models can be computationally compared and evaluated despite being recorded using different vocabularies. These types of comparisons can aid identification of causative variants during exome analysis, even when human mutations may not have been previously identified. The Monarch Initiative accepts queries across the MME and returns possible animal models. It does not initiate queries across the MME.
The MME hopes to expand to include other matchmakers, particularly from areas of the world that are currently under-represented. The MME technical group is working on developing both one-sided hypothesis matching (a candidate gene against genome-wide variant data with no flagged candidate genes) and hypothesis-free matching (unsolved case against unsolved case with phenotypic and genome-wide variant data).