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A Complex Disease Genetics Knowledge Provider for Biomedical Data Translator

Award Number: OT2TR003433
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: OTHER
PERIOD OF PERFORMANCE START DATE: 01/23/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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A Complex Disease Genetics Knowledge Provider for Biomedical Data Translator - A major goal of the Biomedical Data Translator Program is to facilitate disease classification based on molecular and cellular abnormalities. While many experimental approaches exist to interrogate molecular or cellular processes, few can discern which among a host of potential abnormalities are relevant to disease in the human system. Genetic variants associated with disease are unique in providing molecular alterations causally related to human disease risk. There are two types of genetic associations. Rare disease associations can (usually) be clearly linked to a gene and are well represented by catalogs such as ClinVar, OMIM, and Monarch. Complex disease associations are harder to interpret because they (a) are statistical rather than qualitative and (b) usually lie in noncoding genomic regions that cannot be immediately translated to molecular or cellular abnormalities. Many complementary resources to help in the biological translation of complex disease associations have recently emerged, broadly classifiable as either “functional genomic” datasets (e.g. from epigenomic profiling or chromatin capture) or predictive bioinformatic methods (e.g. that integrate various genetic and functional genomic datasets to predict disease-susceptibility genes or pathways). These resources require expertise to curate and interpret, and there is as yet no knowledge source that integrates them to interpret complex disease associations. Furthermore, techniques for harmonizing heterogeneous functional genomic datasets with respect to one another are not yet established, most predictive bioinformatic methods specify complex data-processing pipelines that have not yet been scaled to run across many diseases, and there are few if any “gold standards” to evaluate the molecular or cellular abnormalities identified by these resources. The goal of our proposed project is to address these gaps within a complex disease genetics Knowledge Provider for Translator. We are experts in complex disease genetics and maintain the Knowledge Portal Network (KPN), a collection of open source web portals and Smart APIs that make integrated genetic and genomic datasets publicly accessible for >180 complex diseases. We have built the KPN by developing a protocol for working with disease experts to aggregate and curate high-confidence genetic datasets, building computational pipelines to harmonize these data and apply predictive bioinformatic methods upon them, and extracting relationships mined from these data into a Neo4J graph database. We propose to use the KPN as a foundation to implement a Translator Knowledge Provider of high-confidence complex disease associations and predicted disease-relevant molecular and cellular abnormalities. We will implement this Knowledge Provider by (a) expanding the data sources, data types, and bioinformatic methods integrated within the KPN; (b) developing new computational algorithms to improve the ability of genetic data to identify molecular and cellular abnormalities underlying complex disease; (c) maintaining REST services provisioning Translator with these resources; and (d) developing methodologies for evaluating the accuracy and internal consistency of these data, further curating them, and defining use cases of them within Translator. In so doing, we will enable Translator users to address questions such as: • What genes are causally linked to complex disease [X], and with what confidence? • What is the increase in risk for complex disease [X] when gene [Y] is perturbed? • What pathways are enriched for associations with complex disease [X]? • What tissues mediate the pathogenesis of complex disease [X]? • What other diseases are genetically correlated with complex disease [X]? We participated in the Translator feasibility study and contributed important insights to the project vision including (a) a unifying architectural model of Translator (based on interviews with each Translator team) closely followed by OTA-19-009


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2020	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	000	1	4/9/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,050,680 )
2024	2024	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	002	1	2/14/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	003	1	2/16/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	001	1	12/20/2023	SUPPLEMENT FOR EXPANSION	$1,050,680
2024	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	000	1	11/30/2023	NEW	$0
														Subtotal = $1,050,680

Issue Date FY: 2023 ( Subtotal = $484,013 )
2023	2023	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	001	1	12/7/2022	SUPPLEMENT FOR EXPANSION	$484,013
2023	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	000	1	12/1/2022	NEW	$0
														Subtotal = $484,013

Issue Date FY: 2022 ( Subtotal = $484,013 )
2022	2022	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	001	1	1/28/2022	SUPPLEMENT FOR EXPANSION	$484,013
2022	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	000	1	1/27/2022	NEW	$0
														Subtotal = $484,013

Issue Date FY: 2021 ( Subtotal = $493,324 )
2021	2021	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	001	1	2/9/2021	SUPPLEMENT FOR EXPANSION	$493,324
2021	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	National Center for Advancing Translational Sciences	000	1	2/4/2021	NEW	$0
														Subtotal = $493,324

Grand Total All Awards = $2,512,030

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A Complex Disease Genetics Knowledge Provider for Biomedical Data Translator

Award Number: OT2TR003433

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: OTHER

PERIOD OF PERFORMANCE START DATE: 01/23/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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