Notice Number: NOT-HL-15-253
Release Date: February 12, 2015
Response Date: April 20, 2015
National Heart, Lung, and Blood Institute (NHLBI)
This Request for Information (RFI) seeks feedback to help guide the National Heart, Lung, and Blood Institute (NHLBI) in creating a resource and stimulating discovery in Precision Medicine of heart, lung and blood (HLB) disorders as part of the Whole Genome Sequencing (WGS) Project. This Project is envisioned to encompass deep phenotyping from the molecular to the environmental level which will be shared widely with the scientific community through a data/scientific commons. The commons is intended to support new discovery, facilitate sharing of knowledge gained and provide appropriate attribution for knowledge contributions. The commons will enable Program Directors/Principal Investigators (PDs/PIs) to readily access, analyze and share their own data and analysis tools and also access multiple and diverse data objects including large data sets. As an initial step in this effort the NHLBI is seeking information regarding existing studies (including but not limited to families, founder populations, population isolates, clinical studies and cohorts) with available biospecimens that may be suitable for WGS and RNA sequencing to discover genetic variants influencing complex traits and diseases relevant to NHLBI’s mission. Sample sets must provide adequate statistical power to detect novel variants of small effect on complex diseases and phenotypes that are of high importance to NHLBI in the context of WGS. Sharing data in the NIH’s database of Genotypes and Phenotypes (dbGaP) will be expected, consistent with achieving the goals of this project. The NHLBI especially seeks information about studies of traditionally underrepresented populations and those with high impact HLB phenotypes or disorders. Special emphasis will be given to Blood Disorders (Monogenic and Complex) for this round of the RFI. Those who already responded to NOT-HL-14-030 need not respond again.
The NHLBI has made an early and large investment in the application of genetic and genomic technology to understanding the underlying etiology of heart, lung and blood disorders. The investment has included family-based cohorts and founder populations that have been used successfully for gene discovery by relying on the concepts of heritability and differential transmission of disease susceptibility alleles, as well as large well-phenotyped cohorts and consortia that were used successfully in Genome-Wide Association Studies (GWAS) where large sample sizes are necessary for association studies.
NHLBI believes that the scientific community will benefit considerably from having genome sequence data available for these cohorts, within the context of an appropriate project design. The NHLBI has a strong interest in supporting the discovery of genetic variants influencing HLB disorders in multiple ethnic groups using WGS. WGS studies will allow the analysis of noncoding variants and is increasingly economically feasible at a scale of tens of thousands of individuals, providing sufficient statistical power.
It is important to note that there is still relatively limited genomic information from non-European ancestry groups. There is an opportunity to bridge this gap within the context of the project designs contemplated here (family-based, founder populations, case-control, etc.), with the idea that a good design will aid discovery of variants that will be generally informative about the biology of HLB disease across groups and may be informative about differences in disease prevalence among groups. WGS coupled with other -omic methods such as RNAseq and existing phenotype and outcome data will provide a wealth of information to aid in unraveling the underlying contributors to HLB disease. Ultimately, NHLBI will build a data commons to integrate this genome sequence, other -omic data, and clinical data as a common resource for the scientific community.
The NHLBI seeks information regarding the availability of studies with sample sets of European and non-European origin for a WGS project. Sample sets should afford sufficient statistical power to allow detection of novel variants of small effect on complex diseases and phenotypes of high importance to NHLBI in the context of a WGS study. Such samples should already be part of an ongoing study; studies should have multiple phenotypes previously measured, proven high quality DNA and may have been ascertained at random or by disease status. Studies should have a design and existing genotyping data to allow imputation to large numbers of samples based on deep sequencing on a limited number of informative members. Family-based study designs should include information about appropriate information about pedigree structure and ascertainment. Case-control designs should include information about case definition and control matching. Samples and associated data should be available and transferrable. Participants should have been consented for data sharing, WGS, and multi-use (ability to perform analysis of multiple traits and measures, not just one single disease).
The NHLBI seeks comments on any or all of the following topics but not limited to:
1) The optimal study design and sample size for a WGS project using the samples. Information on ascertainment, minimal samples sizes, case-control definition, family structure, optimal family member sampling/inclusion criteria, and demonstration of appropriate statistical power can be included.
2) The availability of study data and samples with proper consent (include sample sizes, availability, including amount of high quality DNA and RNA) with the above design who are of African Ancestry, American Continental Ancestry (Natives of North and South America), European Ancestry, and/or Other Ancestry (e.g. Asiatic, Pacific Islander, Aboriginal, etc.).
3) The identification of important complex phenotypes (including modifiers of disease) associated with blood diseases such as sickle cell disease, thalassemia, bone marrow failure, hemophilia; thrombosis and graft-versus-host-disease where WGS can contribute significant knowledge to the underlying biology/etiology of the rare or common disease. Reasoning why WGS is required for success and if other genomic technologies have been attempted (WES, GWAS, linkage, etc.).
4) Existing opportunities for replication of findings from the proposed study/ethnic group(s).
5) The barriers (if any) to sharing WGS data from above cited studies in NIH’s dbGaP database. Your comments can include previously consented options in data sharing that may help to overcome these barriers.
6) Most recent publications and/or websites that provide more comprehensive details of the populations. When possible, include relevant PMIDs.
All responses must be submitted via email to NHLBI_WGSRF@mail.nih.gov by April 20, 2015. Please include the Notice number HL-15-030 in the subject line. Response to this RFI is voluntary. Responders are free to address any or all of the categories listed above. Those who already responded to NOT-HL-14-030 need not respond again.
This RFI is for planning purposes only and should not be construed as a solicitation for applications or as an obligation on the part of the Government to provide support for any ideas identified in response to it. Please note that the United States Government will not pay for the preparation of any information submitted or for its use of that information.Responses will be compiled and shared internally and with working groups convened by the NIH, as appropriate. In all cases where responses are shared, the names of the authors will be withheld. We look forward to your input and hope that you will share this document with your colleagues. Updates to this document, if any, will be noted. Please check before submission.
Please direct all inquiries to:
Pankaj Qasba, PhD
National Heart, Lung and Blood Institute (NHLBI)