Heidi E. Steiner

University of Arizona

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Jason H. Karnes

University of Arizona

Jason B. Giles

University of Colorado Anschutz Medical Campus

Dan M. Roden

Vanderbilt University Medical Center

Elizabeth J. Phillips

Vanderbilt University Medical Center

Christian M. Shaffer

Texas Tech University

Kiana L. Martinez

University of Arizona

Larisa H. Cavallari

University of Florida

Ankit A. Desai

Indiana University – Purdue University Indianapolis

Yukihide Momozawa

RIKEN Center for Integrative Medical Sciences

Nancy M. Heddle

McMaster University

Cooperative Institutions

University of Arizona

Vanderbilt University Medical Center

National Institutes of Health

Vanderbilt University

Banner - University Medical Center Tucson

Indiana University – Purdue University Indianapolis

Cincinnati Children's Hospital Medical Center

University of Florida

Universidade de São Paulo

Johns Hopkins University

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Association of Metal Cations with the Anti-PF4/Heparin Antibody Response in Heparin-Induced Thrombocytopenia

Cardiovascular Toxicology (2024)

Jason B. Giles Kiana L. Martinez Heidi E. Steiner Andrew Klein Aikseng Ooi

Heparin-Induced Thrombocytopenia

10.1007/s12012-024-09895-w

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Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension

American Journal of Respiratory and Critical Care Medicine (2020)

Jason H. Karnes Howard W. Wiener Tae-Hwi Schwantes-An Balaji Natarajan Andrew J. Sweatt

Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.

10.1164/rccm.201907-1447oc

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Durchführbarkeit der fetalen Echokardiographie im Rahmen des 11 - 14 Wochen-Ultraschalls

Ultraschall in der Medizin - European Journal of Ultrasound (2006)

Arthur Lederer G. Hasenöhrl Robert Gruber Heidi E. Steiner

Ziel: Die sonographische Diagnostik wird mehr und mehr in das erste Trimenon vorgezogen. Zuletzt wurden zunehmend von Experten durchgeführte Studien über die Echokardiographie im Rahmen des so genannten 11 - 14 Wochen-Schalls publiziert. Ziel dieser Studie war es, die Machbarkeit der frühen Herzuntersuchung anlässlich des Ersttrimenonscreenings im Rahmen des Routinebetriebes zu evaluieren. Material und Methoden: Im Rahmen des Ersttrimenonscreenings wurde zwischen Februar 2003 und März 2004 prospektiv an 128 zugewiesenen, unselektionierten Schwangeren eine Echokardiographie angestrebt. Drei an unserer Abteilung tätige Ärzte unterschiedlicher ÖGUM/DEGUM-Qualifikationen versuchten den Vierkammerblick (4KB) und die Ausflusstrakte (AFT) jeweils mittels B-Bild und Farbdoppler darzustellen. Die Untersuchungsbedingungen entsprachen der „Routine”, vor allem waren sie zeitlich limitiert. Wenn bei der transabdominalen Untersuchung keine ausreichende Bildgebung erreichbar war, wurde auch transvaginal sonographiert. Ergebnisse: Mittels B-Bild wurde in 86/130 der 4KB und in 37/130 die AFTe als erfolgreich dargestellt bezeichnet. Demgegenüber konnte mittels Farbdoppler in 75/130 der 4KB und in 87/130 die AFTe ausreichend dargestellt werden. Schlussfolgerung: Im Routinescreening stellt die frühe Herzuntersuchung eine große Herausforderung dar und in vielen Fällen ist auch bei gutem Equipment keine komplette Darstellung bei der frühen Echokardiographie zu erreichen. Die Zuhilfenahme des Farbdopplers ist vor allem für die Darstellung der Ausflusstrakte hilfreich.

10.1055/s-2006-927028

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Genome-Wide Association Study Identifies Variation in ABO As Risk Factor for Platelet Reactivity in Heparin-Induced Thrombocytopenia

Blood (2020)

Jason B. Giles Jérôme Rollin Christian M. Shaffer Heidi E. Steiner Yukihide Momozawa

Genome-wide Association Study

Genetic Association

10.1182/blood-2020-139651

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Bringing pharmacomicrobiomics to the clinic through well‐designed studies

Clinical and Translational Science (2022)

Heidi E. Steiner Hayley Knight Patterson Jason B. Giles Jason H. Karnes

Pharmacomicrobiomic studies investigate drug-microbiome interactions, such as the effect of microbial variation on drug response and disposition. Studying and understanding the interactions between the gut microbiome and drugs is becoming increasingly relevant to clinical practice due to its potential for avoiding adverse drug reactions or predicting variability in drug response. The highly variable nature of the human microbiome presents significant challenges to assessing microbes' influence. Studies aiming to explore drug-microbiome interactions should be well-designed to account for variation in the microbiome over time and collect data on confounders such as diet, disease, concomitant drugs, and other environmental factors. Here, we assemble a set of important considerations and recommendations for the methodological features required for performing a pharmacomicrobiomic study in humans with a focus on the gut microbiome. Consideration of these factors enable discovery, reproducibility, and more accurate characterization of the relationships between a given drug and the microbiome. Furthermore, appropriate interpretation and dissemination of results from well-designed studies will push the field closer to clinical relevance and implementation.

Gut microbiome

Relevance

Drug Development

10.1111/cts.13381

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Citations (5)

A Nursing In-Service for Diabetes Education

Heidi E. Steiner

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Multi‐site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

Clinical and Translational Science (2020)

Nihal El Rouby Leiliane Rodrigues Marcatto Karla Claudio Letícia Camargo Tavares Heidi E. Steiner

We conducted a multi‐site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States ( n = 411) and Brazil ( n = 663) were genotyped for VKORC1 c.‐1639G> A, common CYP2C9 variants, CYP4F2*3 , and NQO1*2 . Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β = −0.29, P < 2.0 × 10 −16 ; β = −0.21, P = 4.7 × 10 −7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (β = 0.10, P = 2 × 10 −4 ; β = 0.10, P = 0.01, respectively). Associations with VKORC1 (β = −0.14, P = 2.0 × 10 −16 ), CYP2C9 (β = −0.07, P = 5.6 × 10 −10 ), and CYP4F2 (β = 0.03, P = 3 × 10 −3 ), but not NQO1*2 (β = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43–46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin‐treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1 , CYP2C9 , and CYP4F2 with warfarin dose in Latinos from the United States and Brazil.

VKORC1

10.1111/cts.12854

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Genome-wide association study of platelet factor 4/heparin antibodies in heparin-induced thrombocytopenia

Blood Advances (2022)

Jason B. Giles Heidi E. Steiner Jérôme Rollin Christian M. Shaffer Yukihide Momozawa

Heparin, a widely used anticoagulant, carries the risk of an antibody-mediated adverse drug reaction, heparin-induced thrombocytopenia (HIT). A subset of heparin-treated patients produces detectable levels of antibodies against complexes of heparin bound to circulating platelet factor 4 (PF4). Using a genome-wide association study (GWAS) approach, we aimed to identify genetic variants associated with anti-PF4/heparin antibodies that account for the variable antibody response seen in HIT. We performed a GWAS on anti-PF4/heparin antibody levels determined via polyclonal enzyme-linked immunosorbent assays. Our discovery cohort (n = 4237) and replication cohort (n = 807) constituted patients with European ancestry and clinical suspicion of HIT, with cases confirmed via functional assay. Genome-wide significance was considered at α = 5 × 10-8. No variants were significantly associated with anti-PF4/heparin antibody levels in the discovery cohort at a genome-wide significant level. Secondary GWAS analyses included the identification of variants with suggestive associations in the discovery cohort (α = 1 × 10-4). The top variant in both cohorts was rs1555175145 (discovery β = -0.112 [0.018], P = 2.50 × 10-5; replication β = -0.104 [0.051], P = .041). In gene set enrichment analysis, 3 gene sets reached false discovery rate-adjusted significance (q < 0.05) in both discovery and replication cohorts: "Leukocyte Transendothelial Migration," "Innate Immune Response," and "Lyase Activity." Our results indicate that genomic variation is not significantly associated with anti-PF4/heparin antibody levels. Given our power to identify variants with moderate frequencies and effect sizes, this evidence suggests genetic variation is not a primary driver of variable antibody response in heparin-treated patients with European ancestry.

Genome-wide Association Study

Heparin-Induced Thrombocytopenia

10.1182/bloodadvances.2022007673

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Association of Metal Cations with the Anti-PF4/Heparin Antibody Response in Heparin-Induced Thrombocytopenia

Research Square (Research Square) (2024)

Jason B. Giles Kiana L. Martinez Heidi E. Steiner Andrew Klein Aikseng Ooi

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD

Heparin-Induced Thrombocytopenia

10.21203/rs.3.rs-4385055/v1

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Machine Learning for Prediction of Stable Warfarin Dose in US Latinos and Latin Americans

Frontiers in Pharmacology (2021)

Heidi E. Steiner Jason B. Giles Hayley Knight Patterson Jianglin Feng Nihal El Rouby

Populations used to create warfarin dose prediction algorithms largely lacked participants reporting Hispanic or Latino ethnicity. While previous research suggests nonlinear modeling improves warfarin dose prediction, this research has mainly focused on populations with primarily European ancestry. We compare the accuracy of stable warfarin dose prediction using linear and nonlinear machine learning models in a large cohort enriched for US Latinos and Latin Americans (ULLA). Each model was tested using the same variables as published by the International Warfarin Pharmacogenetics Consortium (IWPC) and using an expanded set of variables including ethnicity and warfarin indication. We utilized a multiple linear regression model and three nonlinear regression models: Bayesian Additive Regression Trees, Multivariate Adaptive Regression Splines, and Support Vector Regression. We compared each model's ability to predict stable warfarin dose within 20% of actual stable dose, confirming trained models in a 30% testing dataset with 100 rounds of resampling. In all patients (n = 7,030), inclusion of additional predictor variables led to a small but significant improvement in prediction of dose relative to the IWPC algorithm (47.8 versus 46.7% in IWPC, p = 1.43 × 10-15). Nonlinear models using IWPC variables did not significantly improve prediction of dose over the linear IWPC algorithm. In ULLA patients alone (n = 1,734), IWPC performed similarly to all other linear and nonlinear pharmacogenetic algorithms. Our results reinforce the validity of IWPC in a large, ethnically diverse population and suggest that additional variables that capture warfarin dose variability may improve warfarin dose prediction algorithms.

Resampling

10.3389/fphar.2021.749786

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Citations (14)