Publications by authors named "Bryan Gorman"

4 Publications

  • Page 1 of 1

Genotyping Array Design and Data Quality Control in the Million Veteran Program.

Am J Hum Genet 2020 04;106(4):535-548

VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Brigham and Women's Hospital and Harvard School of Medicine, Boston, MA 02115, USA. Electronic address:

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other 'omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP's substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118558PMC
April 2020

The Placental Atlas Tool (PAT): A collaborative research and discovery platform for the placental research community.

Placenta 2019 05 1;80:42-48. Epub 2019 Apr 1.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Information Resources Management Branch, Bethesda, MD, 20817, USA.

Introduction: The placenta is one of the least understood, yet arguably one of the most important organs for human health and development. While there have been numerous research efforts dedicated to understanding the placenta's critical role, these studies and the data they produced remain separated and largely disparate. In order to facilitate placental research, the Eunice Kennedy Shriver National Institute of Child and Human Development (NICHD) released in October 2018 the Placental Atlas Tool (PAT) (https://pat.nichd.nih.gov/), an internet-based platform offering users a centralized placental database of molecular datasets, analytic tools, and images.

Methods: PAT is a cloud-based system developed by the business requirements defined by NICHD leadership and extramural placental researchers. PAT employs a metadata-driven web interface to provide curated placental datasets and images, enriched with structured, descriptive metadata to enhance data discoverability. PAT also incorporates open source molecular data analytical tools to provide a flexible analytics workflow for placental researchers.

Results: PAT launched with 426 analyzable molecular placental datasets consisting of over 12,500 samples from 10 distinct species, all systematically annotated and processed for enhanced research utility. 828 placental images, consisting of 7 imaging modalities across 47 species, and nearly 300 annotated linked publications supplement the datasets to facilitate knowledge integration and hypothesis generation across disparate molecular studies.

Discussion: PAT will maximize the NICHD's investment in placental research by reinforcing open scientific inquiry, facilitating reuse of datasets, promoting novel research and testing of new hypotheses and analytic methods, and facilitating education of new researchers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.placenta.2019.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527124PMC
May 2019

Multi-scale imaging and informatics pipeline for in situ pluripotent stem cell analysis.

PLoS One 2014 31;9(12):e116037. Epub 2014 Dec 31.

Department Of Pediatric Newborn Medicine and Department of Medicine, Division of Genetics, Brigham and Women's Hospital; Harvard Medical School; Harvard Stem Cell Institute, Boston, Massachusetts, United States of America.

Human pluripotent stem (hPS) cells are a potential source of cells for medical therapy and an ideal system to study fate decisions in early development. However, hPS cells cultured in vitro exhibit a high degree of heterogeneity, presenting an obstacle to clinical translation. hPS cells grow in spatially patterned colony structures, necessitating quantitative single-cell image analysis. We offer a tool for analyzing the spatial population context of hPS cells that integrates automated fluorescent microscopy with an analysis pipeline. It enables high-throughput detection of colonies at low resolution, with single-cellular and sub-cellular analysis at high resolutions, generating seamless in situ maps of single-cellular data organized by colony. We demonstrate the tool's utility by analyzing inter- and intra-colony heterogeneity of hPS cell cycle regulation and pluripotency marker expression. We measured the heterogeneity within individual colonies by analyzing cell cycle as a function of distance. Cells loosely associated with the outside of the colony are more likely to be in G1, reflecting a less pluripotent state, while cells within the first pluripotent layer are more likely to be in G2, possibly reflecting a G2/M block. Our multi-scale analysis tool groups colony regions into density classes, and cells belonging to those classes have distinct distributions of pluripotency markers and respond differently to DNA damage induction. Lastly, we demonstrate that our pipeline can robustly handle high-content, high-resolution single molecular mRNA FISH data by using novel image processing techniques. Overall, the imaging informatics pipeline presented offers a novel approach to the analysis of hPS cells that includes not only single cell features but also colony wide, and more generally, multi-scale spatial configuration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116037PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281228PMC
October 2015

Induced pluripotent stem cells with a mitochondrial DNA deletion.

Stem Cells 2013 Jul;31(7):1287-97

Boston Children's Hospital, Boston, MA, USA.

In congenital mitochondrial DNA (mtDNA) disorders, a mixture of normal and mutated mtDNA (termed heteroplasmy) exists at varying levels in different tissues, which determines the severity and phenotypic expression of disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Induced pluripotent stem (iPS) cells are particularly amenable for studying mtDNA disorders, as cytoplasmic genetic material is retained during direct reprogramming. Here, we derive and characterize iPS cells from a patient with PS. Taking advantage of the tendency for heteroplasmy to change with cell passage, we isolated isogenic PS-iPS cells without detectable levels of deleted mtDNA. We found that PS-iPS cells carrying a high burden of deleted mtDNA displayed differences in growth, mitochondrial function, and hematopoietic phenotype when differentiated in vitro, compared to isogenic iPS cells without deleted mtDNA. Our results demonstrate that reprogramming somatic cells from patients with mtDNA disorders can yield pluripotent stem cells with varying burdens of heteroplasmy that might be useful in the study and treatment of mitochondrial diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/stem.1354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692613PMC
July 2013