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  1. AU="Sharber, Brian"
  2. AU="Goyaux, Nathalie"
  3. AU="Rauch, Geraldine"
  4. AU="Ekoh, Okwukwe Faith"
  5. AU="A Rahim, Haslinda"
  6. AU="Richard Stahl"
  7. AU=Vazquez-Iglesias J L
  8. AU="Amundsen, David S"
  9. AU="Konios, Dimitrios"
  10. AU="Lindh, Ingrid"
  11. AU=Zhao Chunyan
  12. AU="Scalia, Jennifer B"
  13. AU="Balint, Lajos"
  14. AU="Liang, Siping"
  15. AU="Wong, Anthony"
  16. AU="Müjdat YENİCESU"
  17. AU="Brooks, M L"
  18. AU="Garcia-Gutierrez, Ania" AU="Garcia-Gutierrez, Ania"
  19. AU="Marina Paola Gardiman"
  20. AU="Labarthe, Simon"
  21. AU="Jiahui Li"
  22. AU="Geier, Johannes"
  23. AU=Thangaraju Pugazhenthan
  24. AU="Tapio, Joona"
  25. AU="Navaratnam, Dhasakumar"
  26. AU="Blank, Marissa Cathleen"
  27. AU="Sadeghi, Yasaman"
  28. AU=Ye Keqiang
  29. AU="Huda, Walter"
  30. AU="Petrova, Polina E"
  31. AU="Pond, Gregory"
  32. AU=Krzewski Konrad
  33. AU="Feng, Yuquan"
  34. AU="Schmermund, Ben Niklas"
  35. AU="Soni, Payal D"
  36. AU="Romero-García, Carolina"
  37. AU="Petty, Lloyd"
  38. AU="James E. Posey"

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  1. Artikel ; Online: Solid organ transplant recipients exhibit more TET2-mutant clonal hematopoiesis of indeterminate potential not driven by increased transplantation risk.

    Silver, Alexander J / Vlasschaert, Caitlyn / Mack, Taralynn / Sharber, Brian / Xu, Yaomin / Bick, Alexander G / Pinson, C Wright / Savona, Michael R

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2024  

    Abstract: Purpose: Solid organ transplant recipients comprise a unique population of immunosuppressed patients with increased risk of malignancy, including hematologic neoplasms. Clonal hematopoiesis of indeterminate potential (CHIP) represents a known risk ... ...

    Abstract Purpose: Solid organ transplant recipients comprise a unique population of immunosuppressed patients with increased risk of malignancy, including hematologic neoplasms. Clonal hematopoiesis of indeterminate potential (CHIP) represents a known risk factor for hematologic malignancy and this study describes the prevalence and patterns of CHIP mutations across several types of solid organ transplants.
    Experimental design: We use two national biobank cohorts comprised of >650,000 participants with linked genomic and longitudinal phenotypic data to describe the features of CHIP across 2,610 individuals who received kidney, liver, heart, or lung allografts.
    Results: We find individuals with an allograft prior to their biobank enrollment had an increased prevalence of TET2 mutations (OR 1.90; p = 4.0e-4), but individuals who received transplants post-enrollment had a CHIP mutation spectrum similar to that of the general population, without enrichment of TET2. Additionally, we do not observe an association between CHIP and risk of incident transplantation among the overall population (HR 1.02; p = 0.91). And in an exploratory analysis, we do not find evidence for a strong association between CHIP and rates of transplant complications such as rejection or graft failure.
    Conclusions: These results demonstrate that recipients of solid organ transplants display a unique pattern of clonal hematopoiesis with enrichment of TET2 driver mutations, the causes of which remain unclear and are deserving of further study.
    Sprache Englisch
    Erscheinungsdatum 2024-03-29
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-23-3840
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Multiomic Profiling of Human Clonal Hematopoiesis Reveals Genotype and Cell-Specific Inflammatory Pathway Activation.

    Heimlich, Jonathan Brett / Bhat, Pawan / Parker, Alyssa / Jenkins, Matthew T / Vlasschaert, Caitlyn / Ulloa, Jessica / Van Amburg, Joseph / Potts, Chad R / Olson, Sydney / Silver, Alexander J / Ahmad, Ayesha / Sharber, Brian / Brown, Donovan / Hu, Ningning / van Galen, Peter / Savona, Michael R / Bick, Alexander G / Ferrell, Paul Brent

    Blood advances

    2024  

    Abstract: Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood ... ...

    Abstract Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood gene expression in 66,968 single cells from a cohort of 17 CH patients and 7 controls. Using a novel mitochondrial DNA barcoding approach, we were able to identify and separately compare mutant TET2 and DNMT3A cells to non-mutant counterparts. We discovered the vast majority of mutated cells were in the myeloid compartment. Additionally, patients harboring DNMT3A and TET2 CH mutations possessed a pro-inflammatory profile in CD14+ monocytes through previously unrecognized pathways such as galectin and macrophage Inhibitory Factor (MIF). We also found that T cells from CH patients, though mostly un-mutated, had decreased expression of GTPase of the immunity associated protein (GIMAP) genes, which are critical to T cell development, suggesting that CH impairs T cell function.
    Sprache Englisch
    Erscheinungsdatum 2024-03-20
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2023011445
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic data sets.

    Vlasschaert, Caitlyn / Mack, Taralynn / Heimlich, J Brett / Niroula, Abhishek / Uddin, Md Mesbah / Weinstock, Joshua / Sharber, Brian / Silver, Alexander J / Xu, Yaomin / Savona, Michael / Gibson, Christopher / Lanktree, Matthew B / Rauh, Michael J / Ebert, Benjamin L / Natarajan, Pradeep / Jaiswal, Siddhartha / Bick, Alexander G

    Blood

    2023  Band 141, Heft 18, Seite(n) 2214–2223

    Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples that are sequenced using ... ...

    Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples that are sequenced using approaches that cover the whole genome, the whole exome, or targeted genetic regions; however, differentiating true CHIP mutations from sequencing artifacts and germ line variants is a considerable bioinformatic challenge. We present a stepwise method that combines filtering based on sequencing metrics, variant annotation, and population-based associations to increase the accuracy of CHIP calls. We apply this approach to ascertain CHIP in ∼550 000 individuals in the UK Biobank complete whole exome cohort and the All of Us Research Program initial whole genome release cohort. CHIP ascertainment on this scale unmasks recurrent artifactual variants and highlights the importance of specialized filtering approaches for several genes, including TET2 and ASXL1. We show how small changes in filtering parameters can considerably increase CHIP misclassification and reduce the effect size of epidemiological associations. Our high-fidelity call set refines previous population-based associations of CHIP with incident outcomes. For example, the annualized incidence of myeloid malignancy in individuals with small CHIP clones is 0.03% per year, which increases to 0.5% per year among individuals with very large CHIP clones. We also find a significantly lower prevalence of CHIP in individuals of self-reported Latino or Hispanic ethnicity in All of Us, highlighting the importance of including diverse populations. The standardization of CHIP calling will increase the fidelity of CHIP epidemiological work and is required for clinical CHIP diagnostic assays.
    Mesh-Begriff(e) Humans ; Clonal Hematopoiesis/genetics ; Hematopoiesis/genetics ; Population Health ; Mutation ; Human Genetics
    Sprache Englisch
    Erscheinungsdatum 2023-03-01
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2022018825
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel: Interoperability of phenome-wide multimorbidity patterns: a comparative study of two large-scale EHR systems.

    Strayer, Nick / Vessels, Tess / Choi, Karmel / Zhang, Siwei / Li, Yajing / Sharber, Brian / Hsi, Ryan S / Bejan, Cosmin A / Bick, Alexander G / Balko, Justin M / Johnson, Douglas B / Wheless, Lee E / Wells, Quinn S / Shah, Ravi / Philips, Elizabeth J / Self, Wesley H / Pulley, Jill M / Wilkins, Consuelo H / Chen, Qingxia /
    Hartert, Tina / Savona, Michael R / Shyr, Yu / Roden, Dan M / Smoller, Jordan W / Ruderfer, Douglas M / Xu, Yaomin

    medRxiv : the preprint server for health sciences

    2024  

    Abstract: Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administration raise questions about the consistency and ... ...

    Abstract Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administration raise questions about the consistency and reproducibility of EHR-based multimorbidity research.
    Methods: Utilizing phecodes to represent the disease phenome, we analyzed pairwise comorbidity strengths using a dual logistic regression approach and constructed multimorbidity as an undirected weighted graph. We assessed the consistency of the multimorbidity networks within and between two major EHR systems at local (nodes and edges), meso (neighboring patterns), and global (network statistics) scales. We present case studies to identify disease clusters and uncover clinically interpretable disease relationships. We provide an interactive web tool and a knowledge base combing data from multiple sources for online multimorbidity analysis.
    Findings: Analyzing data from 500,000 patients across Vanderbilt University Medical Center and Mass General Brigham health systems, we observed a strong correlation in disease frequencies ( Kendall's τ = 0.643) and comorbidity strengths (Pearson ρ = 0.79). Consistent network statistics across EHRs suggest a similar structure of multimorbidity networks at various scales. Comorbidity strengths and similarities of multimorbidity connection patterns align with the disease genetic correlations. Graph-theoretic analyses revealed a consistent core-periphery structure, implying efficient network clustering through threshold graph construction. Using hydronephrosis as a case study, we demonstrated the network's ability to uncover clinically relevant disease relationships and provide novel insights.
    Interpretation: Our findings demonstrate the robustness of large-scale EHR data for studying complex disease interactions. The alignment of multimorbidity patterns with genetic data suggests the potential utility for uncovering shared etiology of diseases. The consistent core-periphery network structure offers a strategic approach to analyze disease clusters. This work also sets the stage for advanced disease modeling, with implications for precision medicine.
    Funding: VUMC Biostatistics Development Award, UL1 TR002243, R21DK127075, R01HL140074, P50GM115305, R01CA227481.
    Sprache Englisch
    Erscheinungsdatum 2024-03-30
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2024.03.28.24305045
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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