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1. A Game-Theoretic Perspective for Efficient Modern Random Access

Author

Hansen, Andreas Peter Juhl, Münster, Jeppe Roden, Villadsen, Rasmus Erik, Segaard, Simon Bock, Rasmussen, Søren Pilegaard, Biscio, Christophe, and Leyva-Mayorga, Israel

Subjects
Computer Science - Information Theory, Computer Science - Computer Science and Game Theory
Abstract

Modern random access mechanisms combine packet repetitions with multi-user detection mechanisms at the receiver to maximize the throughput and reliability in massive Internet of Things (IoT) scenarios. However, optimizing the access policy, which selects the number of repetitions, is a complicated problem, and failing to do so can lead to an inefficient use of resources and, potentially, to an increased congestion. In this paper, we follow a game-theoretic approach for optimizing the access policies of selfish users in modern random access mechanisms. Our goal is to find adequate values for the rewards given after a success to achieve a Nash equilibrium (NE) that optimizes the throughput of the system while considering the cost of transmission. Our results show that a mixed strategy, where repetitions are selected according to the irregular repetition slotted ALOHA (IRSA) protocol, attains a NE that maximizes the throughput in the special case with two users. In this scenario, our method increases the throughput by 30% when compared to framed ALOHA. Furthermore, we present three methods to attain a NE with near-optimal throughput for general modern random access scenarios, which exceed the throughput of framed ALOHA by up to 34%., Comment: Submitted for publication to IEEE WCNC 2025

Published
2024

2. Invasive Assessment of Coronary Artery Disease in Clonal Hematopoiesis of Indeterminate Potential.

Author

Heimlich, J Brett, Raddatz, Michael A, Wells, John, Vlasschaert, Caitlyn, Olson, Sydney, Threadcraft, Marcus, Foster, Kristoff, Boateng, Emmanuel, Umbarger, Kelsey, Su, Yan Ru, Roden, Dan M, Barker, Colin M, and Bick, Alexander G

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Cardiovascular, Stem Cell Research, Atherosclerosis, Genetics, Heart Disease - Coronary Heart Disease, Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, atherosclerosis, genetics, heart failure, mutation, observational cohort, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk of atherosclerotic cardiovascular disease. However, there are limited data regarding specific cardiovascular phenotypes. The purpose of this study was to define the coronary artery disease phenotype of the CHIP population-based on coronary angiography.MethodsWe recruited 1142 patients from the Vanderbilt University Medical Center cardiac catheterization laboratory and performed DNA sequencing to determine CHIP status. Multivariable logistic regression models and proportional odds models were used to assess the association between CHIP status and angiography phenotypes.ResultsWe found that 18.4% of patients undergoing coronary angiography had a CHIP mutation. Those with CHIP had a higher risk of having obstructive left main (odds ratio, 2.44 [95% CI, 1.40-4.27]; P=0.0018) and left anterior descending (odds ratio, 1.59 [1.12-2.24]; P=0.0092) coronary artery disease compared with non-CHIP carriers. We additionally found that a specific CHIP mutation, ten eleven translocase 2 (TET2), has a larger effect size on left main stenosis compared with other CHIP mutations.ConclusionsThis is the first invasive assessment of coronary artery disease in CHIP and offers a description of a specific atherosclerotic phenotype in CHIP wherein there is an increased risk of obstructive left main and left anterior descending artery stenosis, especially among TET2 mutation carriers. This serves as a basis for understanding enhanced morbidity and mortality in CHIP.

Published
2024

3. Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate

Author

Mack, Taralynn M, Raddatz, Michael A, Pershad, Yash, Nachun, Daniel C, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O’Connell, Jeffrey R, Kenny, Eimear E, Loos, Ruth JF, Redline, Susan, Cade, Brian E, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Cho, Michael H, DeMeo, Dawn L, Levy, Daniel, Johnson, Andrew D, Mathias, Rasika A, Yanek, Lisa R, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Raffield, Laura M, Carson, April P, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Roden, Dan M, Kooperberg, Charles, Auer, Paul L, Desai, Pinkal, Blackwell, Thomas W, Smith, Albert V, Reiner, Alexander P, Jaiswal, Siddhartha, Weinstock, Joshua S, and Bick, Alexander G

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Hematology, Genetics, Biotechnology, Aging, Human Genome, Stem Cell Research, Precision Medicine, Aetiology, 2.1 Biological and endogenous factors, Cancer, Good Health and Well Being, Clinical sciences
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

Published
2024

4. Determinants of mosaic chromosomal alteration fitness.

Author

Pershad, Yash, Mack, Taralynn, Poisner, Hannah, Jakubek, Yasminka, Stilp, Adrienne, Mitchell, Braxton, Lewis, Joshua, Boerwinkle, Eric, Loos, Ruth, Chami, Nathalie, Wang, Zhe, Barnes, Kathleen, Pankratz, Nathan, Fornage, Myriam, Redline, Susan, Psaty, Bruce, Bis, Joshua, Shojaie, Ali, Silverman, Edwin, Cho, Michael, Yun, Jeong, DeMeo, Dawn, Levy, Daniel, Johnson, Andrew, Mathias, Rasika, Taub, Margaret, Arnett, Donna, North, Kari, Raffield, Laura, Carson, April, Doyle, Margaret, Rich, Stephen, Guo, Xiuqing, Cox, Nancy, Roden, Dan, Franceschini, Nora, Desai, Pinkal, Reiner, Alex, Auer, Paul, Scheet, Paul, Jaiswal, Siddhartha, Weinstock, Joshua, Bick, Alexander, and Rotter, Jerome

Subjects
Humans, Mosaicism, Chromosome Aberrations, Clonal Hematopoiesis, Male, Female, Genome-Wide Association Study, Janus Kinase 2, Telomerase, Loss of Heterozygosity, Cross-Sectional Studies, Mutation, Middle Aged, Hematopoietic Stem Cells, Polymorphism, Single Nucleotide, Aged
Abstract

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Published
2024

5. Fatal Infections Differentially Involve Allograft and Native Lungs in Single Lung Transplant Recipients

Author

Villalba, Julian A., Cheek-Norgan, E. Heidi, Johnson, Tucker F., Yi, Eunhee S., Boland, Jennifer M., Aubry, Marie-Christine, Pennington, Kelly M., Scott, John P., and Roden, Anja C.

Subjects
Lungs -- Transplantation, Respiratory tract infections -- Risk factors -- Development and progression, Health
Abstract

* Context.--Respiratory infections complicate lung transplantation and increase the risk of allograft dysfunction. Allograft lungs may have different susceptibilities to infection than native lungs, potentially leading to different disease severity in lungs of single lung transplant recipients (SLTRs). Objective.--To study whether infections affect allograft and native lungs differently in SLTRs but similarly in double LTRs (DLTRs). Design.--Using an institutional database of LTRs, medical records were searched, chest computed tomography studies were systematically reviewed, and histopathologic features were recorded per lung lobe and graded semiquantitatively. A multilobar-histopathology score (MLHS) including histopathologic data from each lung and a bilateral ratio ([MLHS.sub.ratio]) comparing histopathologies between both lungs were calculated in SLTRs and compared to DLTRs. Results.--Six SLTRs died of infection involving the lungs. All allografts showed multifocal histopathologic evidence of infection, but at least 1 lobe of the native lung was uninvolved. In 4 of 5 DLTRs, histopathologic evidence of infection was seen in all lung lobes. On computed tomography, multifocal ground-glass and/or nodular opacities were found in a bilateral distribution in all DLTRs but in only 2 of 6 SLTRs. In SLTRs, the [MLHS.sub.Allograft] was higher than [MLHS.sub.Native] (P = .02). The [MLHS.sub.ratio] values of SLTR and DLTR were significantly different (P < .001). Conclusions.--Allograft and native lungs appear to harbor different susceptibilities to infections. The results are important for the management of LTRs. doi: 10.5858/arpa.2023-0227-OA), The median overall survival of lung transplant recipients (LTRs) is only 6.7 years, which is shorter than for other solid organ transplantations. (1) Noncytomegalovirus (nonCMV) infections play a major role [...]

Published
2024
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6. Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate

Author

Mack, Taralynn M., Raddatz, Michael A., Pershad, Yash, Nachun, Daniel C., Taylor, Kent D., Guo, Xiuqing, Shuldiner, Alan R., O’Connell, Jeffrey R., Kenny, Eimear E., Loos, Ruth J. F., Redline, Susan, Cade, Brian E., Psaty, Bruce M., Bis, Joshua C., Brody, Jennifer A., Silverman, Edwin K., Yun, Jeong H., Cho, Michael H., DeMeo, Dawn L., Levy, Daniel, Johnson, Andrew D., Mathias, Rasika A., Yanek, Lisa R., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Raffield, Laura M., Carson, April P., Rotter, Jerome I., Rich, Stephen S., Manichaikul, Ani W., Gu, C. Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M. Benjamin, Roden, Dan M., Kooperberg, Charles, Auer, Paul L., Desai, Pinkal, Blackwell, Thomas W., Smith, Albert V., Reiner, Alexander P., Jaiswal, Siddhartha, Weinstock, Joshua S., and Bick, Alexander G.

Published
2024
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8. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Author

Keener, Rebecca, Chhetri, Surya B, Connelly, Carla J, Taub, Margaret A, Conomos, Matthew P, Weinstock, Joshua, Ni, Bohan, Strober, Benjamin, Aslibekyan, Stella, Auer, Paul L, Barwick, Lucas, Becker, Lewis C, Blangero, John, Bleecker, Eugene R, Brody, Jennifer A, Cade, Brian E, Celedon, Juan C, Chang, Yi-Cheng, Cupples, L Adrienne, Custer, Brian, Freedman, Barry I, Gladwin, Mark T, Heckbert, Susan R, Hou, Lifang, Irvin, Marguerite R, Isasi, Carmen R, Johnsen, Jill M, Kenny, Eimear E, Kooperberg, Charles, Minster, Ryan L, Naseri, Take, Viali, Satupa’itea, Nekhai, Sergei, Pankratz, Nathan, Peyser, Patricia A, Taylor, Kent D, Telen, Marilyn J, Wu, Baojun, Yanek, Lisa R, Yang, Ivana V, Albert, Christine, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Bis, Joshua C, Blackwell, Thomas W, Boerwinkle, Eric, Burchard, Esteban G, Carson, April P, Chen, Zhanghua, Chen, Yii-Der Ida, Darbar, Dawood, de Andrade, Mariza, Ellinor, Patrick T, Fornage, Myriam, Gelb, Bruce D, Gilliland, Frank D, He, Jiang, Islam, Talat, Kaab, Stefan, Kardia, Sharon LR, Kelly, Shannon, Konkle, Barbara A, Kumar, Rajesh, Loos, Ruth JF, Martinez, Fernando D, McGarvey, Stephen T, Meyers, Deborah A, Mitchell, Braxton D, Montgomery, Courtney G, North, Kari E, Palmer, Nicholette D, Peralta, Juan M, Raby, Benjamin A, Redline, Susan, Rich, Stephen S, Roden, Dan, Rotter, Jerome I, Ruczinski, Ingo, Schwartz, David, Sciurba, Frank, Shoemaker, M Benjamin, Silverman, Edwin K, Sinner, Moritz F, Smith, Nicholas L, Smith, Albert V, Tiwari, Hemant K, Vasan, Ramachandran S, Weiss, Scott T, Williams, L Keoki, Zhang, Yingze, Ziv, Elad, Raffield, Laura M, Reiner, Alexander P, Arvanitis, Marios, Greider, Carol W, Mathias, Rasika A, and Battle, Alexis

Subjects
Biological Sciences, Genetics, Human Genome, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Humans, Genome-Wide Association Study, Telomere, K562 Cells, Telomere Homeostasis, Polymorphism, Single Nucleotide, Gene Expression Regulation, CRISPR-Cas Systems, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group
Abstract

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Published
2024

9. A multisociety Delphi consensus statement on new fatty liver disease nomenclature

Author

Rinella, Mary E, Lazarus, Jeffrey V, Ratziu, Vlad, Francque, Sven M, Sanyal, Arun J, Kanwal, Fasiha, Romero, Diana, Abdelmalek, Manal F, Anstee, Quentin M, Arab, Juan Pablo, Arrese, Marco, Bataller, Ramon, Beuers, Ulrich, Boursier, Jerome, Bugianesi, Elisabetta, Byrne, Christopher D, Narro, Graciela E Castro, Chowdhury, Abhijit, Cortez-Pinto, Helena, Cryer, Donna R, Cusi, Kenneth, El-Kassas, Mohamed, Klein, Samuel, Eskridge, Wayne, Fan, Jiangao, Gawrieh, Samer, Guy, Cynthia D, Harrison, Stephen A, Kim, Seung Up, Koot, Bart G, Korenjak, Marko, Kowdley, Kris V, Lacaille, Florence, Loomba, Rohit, Mitchell-Thain, Robert, Morgan, Timothy R, Powell, Elisabeth E, Roden, Michael, Romero-Gómez, Manuel, Silva, Marcelo, Singh, Shivaram Prasad, Sookoian, Silvia C, Spearman, C Wendy, Tiniakos, Dina, Valenti, Luca, Vos, Miriam B, Wong, Vincent Wai-Sun, Xanthakos, Stavra, Yilmaz, Yusuf, Younossi, Zobair, Hobbs, Ansley, Villota-Rivas, Marcela, Newsome, Philip N, and group, NAFLD Nomenclature consensus

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Liver Disease, Digestive Diseases, Clinical Research, Hepatitis, Chronic Liver Disease and Cirrhosis, Substance Misuse, Oral and gastrointestinal, Good Health and Well Being, Female, Male, Humans, Non-alcoholic Fatty Liver Disease, Delphi Technique, Ethanol, Consensus, Hepatomegaly, NAFLD Nomenclature consensus group, ALD, Delphi, MASH, MASLD, Met-ALD, NAFLD, alcohol, metabolic, nomenclature, stigma, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences
Abstract

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.

Published
2023

10. A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

Author

Rinella, Mary, Lazarus, Jeffrey, Ratziu, Vlad, Francque, Sven, Sanyal, Arun, Kanwal, Fasiha, Romero, Diana, Abdelmalek, Manal, Anstee, Quentin, Arab, Juan, Arrese, Marco, Bataller, Ramon, Beuers, Ulrich, Boursier, Jerome, Bugianesi, Elisabetta, Byrne, Christopher, Castro Narro, Graciela, Chowdhury, Abhijit, Cortez-Pinto, Helena, Cryer, Donna, Cusi, Kenneth, El-Kassas, Mohamed, Klein, Samuel, Eskridge, Wayne, Fan, Jiangao, Gawrieh, Samer, Guy, Cynthia, Harrison, Stephen, Kim, Seung, Koot, Bart, Korenjak, Marko, Kowdley, Kris, Lacaille, Florence, Powell, Elisabeth, Roden, Michael, Romero-Gómez, Manuel, Silva, Marcelo, Singh, Shivaram, Sookoian, Silvia, Spearman, C, Tiniakos, Dina, Valenti, Luca, Vos, Miriam, Wong, Vincent, Xanthakos, Stavra, Yilmaz, Yusuf, Younossi, Zobair, Hobbs, Ansley, Villota-Rivas, Marcela, Newsome, Philip, Mitchell-Thain, Robert, Morgan, Timothy, and Loomba, Rohit

Subjects
Male, Female, Humans, Non-alcoholic Fatty Liver Disease, Delphi Technique, Hepatomegaly, Surveys and Questionnaires
Abstract

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms nonalcoholic and fatty were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

Published
2023

11. The Journey to a FAIR CORE DATA SET for Diabetes Research in Germany

Author

Esther Thea Inau, Angela Dedié, Ivona Anastasova, Renate Schick, Yaroslav Zdravomyslov, Brigitte Fröhlich, Andreas L. Birkenfeld, Martin Hrabě de Angelis, Michael Roden, Atinkut Alamirrew Zeleke, Martin Preusse, and Dagmar Waltemath

Subjects
Science
Abstract

Abstract The German Center for Diabetes Research (DZD) established a core data set (CDS) of clinical parameters relevant for diabetes research in 2021. The CDS is central to the design of current and future DZD studies. Here, we describe the process and outcomes of FAIRifying the initial version of the CDS. We first did a baseline evaluation of the FAIRness using the FAIR Data Maturity Model. The FAIRification process and the results of this assessment led us to convert the CDS into the recommended format for spreadsheets, annotating the parameters with standardized medical codes, licensing the data set, enriching the data set with metadata, and indexing the metadata. The FAIRified version of the CDS is more suitable for data sharing in diabetes research across DZD sites and beyond. It contributes to the reusability of health research studies.

Published
2024
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12. ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants

Author

Matthew J. O’Neill, Tao Yang, Julie Laudeman, Maria E. Calandranis, M. Lorena Harvey, Joseph F. Solus, Dan M. Roden, and Andrew M. Glazer

Subjects
Science
Abstract

Abstract Interpreting the clinical significance of putative splice-altering variants outside canonical splice sites remains difficult without time-intensive experimental studies. To address this, we introduce Parallel Splice Effect Sequencing (ParSE-seq), a multiplexed assay to quantify variant effects on RNA splicing. We first apply this technique to study hundreds of variants in the arrhythmia-associated gene SCN5A. Variants are studied in ‘minigene’ plasmids with molecular barcodes to allow pooled variant effect quantification. We perform experiments in two cell types, including disease-relevant induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The assay strongly separates known control variants from ClinVar, enabling quantitative calibration of the ParSE-seq assay. Using these evidence strengths and experimental data, we reclassify 29 of 34 variants with conflicting interpretations and 11 of 42 variants of uncertain significance. In addition to intronic variants, we show that many synonymous and missense variants disrupted RNA splicing. Two splice-altering variants in the assay also disrupt splicing and sodium current when introduced into iPSC-CMs by CRISPR-Cas9 editing. ParSE-seq provides high-throughput experimental data for RNA-splicing to support precision medicine efforts and can be readily adopted to study other loss-of-function genotype-phenotype relationships.

Published
2024
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13. Pulmonary light chain deposition disease: Case series and review of the literature

Author

Tomas V. Gonzalez, MD, Anja C. Roden, MD, Brian J. Bartholmai, MD, and Rebecca M. Lindell, MD

Subjects
CT, Radiography, Lungs, Thorax, Immunoglobulin, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Pulmonary light chain deposition disease is a rare entity characterized by immunoglobulin deposition within the lung parenchyma with pathologic features distinct from pulmonary amyloidosis. Here, the authors present the clinical presentation, associations, and radiologic features of pulmonary light chain deposition disease in a series of 4 patients as well as discuss the distinctions from amyloidosis. The present case series highlights the frequent presence of both cysts and nodules at CT. Clinically, lymphoma and/or autoimmune disease are often associated.

Published
2024
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14. An Online Research Immersion Program to Increase Introductory Science Student Confidence and Science Identity

Author

Erica J. Zheng, Elizabeth Oakes, and Julie Roden

Abstract

The number of undergraduate students from underrepresented backgrounds enrolled in science and technology-related courses has increased over the past 20 years, but these students' persistence in STEM majors until graduation still lags behind the overall college population. Interventions like exposure to independent research, instruction using active learning, and connection within a scientific community have been shown to increase persistence and the development of science identity, especially for underrepresented minority students (URM), students with high financial need, and first-generation college students. However, exposure to research for introductory students can be expensive or challenging for an institution to provide and for some students to access. We designed Wintersession Research Week as a remotely taught, collaborative introduction to independent research for beginning undergraduate students, prioritizing those traditionally underrepresented in STEM (low income, first generation, and URM students). Because this program utilized graduate students as research mentors, we also provided training and mentoring to develop the next generation of science faculty. We found that the program helped undergraduate student participants to develop a scientific identity and increase confidence in their skills, and that graduate students found the experience valuable for their future teaching. We believe that elements of this program are adaptable to both virtual and in-person settings as an introduction to research, mentorship, and teaching for students and mentors.

Published
2024
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15. Kingdom of God: Christian anarchism is as old as Christianity itself

Author

Roden, Renee

Subjects
Sermon on the mount, Kingdom of God, Christians, Dukhobors, Philosophy and religion
Abstract

In the foothills of British Columbia's Rocky Mountains, about two miles north of the border with the United States, there is a small commune known as Hardy Mountain Doukhobor Village. [...]

Published
2024

16. Bayesian parameter identification in impedance boundary conditions for Helmholtz problems

Author

Wulbusch, Nick, Roden, Reinhild, Blau, Matthias, and Chernov, Alexey

Subjects
Mathematics - Numerical Analysis, 35J05, 65C05, 35R60, 62F15, 65N21, 65N30
Abstract

We consider the problem of identifying the acoustic impedance of a wall surface from noisy pressure measurements in a closed room using a Bayesian approach. The room acoustics is modeled by the interior Helmholtz equation with impedance boundary conditions. The aim is to compute moments of the acoustic impedance to estimate a suitable density function of the impedance coefficient. For the computation of moments we use ratio estimators and Monte-Carlo sampling. We consider two different experimental scenarios. In the first scenario, the noisy measurements correspond to a wall modeled by impedance boundary conditions. In this case, the Bayesian algorithm uses a model that is (up to the noise) consistent with the measurements and our algorithm is able to identify acoustic impedance with high accuracy. In the second scenario, the noisy measurements come from a coupled acoustic-structural problem, modeling a wall made of glass, whereas the Bayesian algorithm still uses a model with impedance boundary conditions. In this case, the parameter identification model is inconsistent with the measurements and therefore is not capable to represent them well. Nonetheless, for particular frequency bands the Bayesian algorithm identifies estimates with high likelihood. Outside these frequency bands the algorithm fails. We discuss the results of both examples and possible reasons for the failure of the latter case for particular frequency values., Comment: 22 pages, 16 figures

Published
2023

17. A Controlled Experiment on the Impact of Intrusion Detection False Alarm Rate on Analyst Performance

Author

Layman, Lucas and Roden, William

Subjects
Computer Science - Cryptography and Security
Abstract

Organizations use intrusion detection systems (IDSes) to identify harmful activity among millions of computer network events. Cybersecurity analysts review IDS alarms to verify whether malicious activity occurred and to take remedial action. However, IDS systems exhibit high false alarm rates. This study examines the impact of IDS false alarm rate on human analyst sensitivity (probability of detection), precision (positive predictive value), and time on task when evaluating IDS alarms. A controlled experiment was conducted with participants divided into two treatment groups, 50% IDS false alarm rate and 86% false alarm rate, who classified whether simulated IDS alarms were true or false alarms. Results show statistically significant differences in precision and time on task. The median values for the 86% false alarm rate group were 47% lower precision and 40% slower time on task than the 50% false alarm rate group. No significant difference in analyst sensitivity was observed., Comment: 8 pages, 4 figures

Published
2023

34. Artificial intelligence-based epigenomic, transcriptomic and histologic signatures of tobacco use in oral squamous cell carcinoma

Author

Viet, Chi T., Asam, Kesava R., Yu, Gary, Dyer, Emma C., Kochanny, Sara, Thomas, Carissa M., Callahan, Nicholas F., Morlandt, Anthony B., Cheng, Allen C., Patel, Ashish A., Roden, Dylan F., Young, Simon, Melville, James, Shum, Jonathan, Walker, Paul C., Nguyen, Khanh K., Kidd, Stephanie N., Lee, Steve C., Folk, Gretchen S., Viet, Dan T., Grandhi, Anupama, Deisch, Jeremy, Ye, Yi, Momen-Heravi, Fatemeh, Pearson, Alexander T., and Aouizerat, Bradley E.

Published
2024
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36. Clinical associations with a polygenic predisposition to benign lower white blood cell counts

Author

Mosley, Jonathan D., Shelley, John P., Dickson, Alyson L., Zanussi, Jacy, Daniel, Laura L., Zheng, Neil S., Bastarache, Lisa, Wei, Wei-Qi, Shi, Mingjian, Jarvik, Gail P., Rosenthal, Elisabeth A., Khan, Atlas, Sherafati, Alborz, Kullo, Iftikhar J., Walunas, Theresa L., Glessner, Joseph, Hakonarson, Hakon, Cox, Nancy J., Roden, Dan M., Frangakis, Stephan G., Vanderwerff, Brett, Stein, C. Michael, Van Driest, Sara L., Borinstein, Scott C., Shu, Xiao-Ou, Zawistowski, Matthew, Chung, Cecilia P., and Kawai, Vivian K.

Published
2024
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38. Human tear film protein sampling using soft contact lenses

Author

Roden, Robert K., Zuniga, Nathan, Wright, Joshua C., Parkinson, David H., Jiang, Fangfang, Patil, Leena M., Burlett, Rebecca S., Nitz, Alyssa A., Rogers, Joshua J., Pittman, Jarett T., Virgin, Kenneth L., Ackroyd, P. Christine, Payne, Samuel H., Price, John C., and Christensen, Kenneth A.

Published
2024
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42. The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young

Author

Puckelwartz, Megan J., Pesce, Lorenzo L., Hernandez, Edgar J., Webster, Gregory, Dellefave-Castillo, Lisa M., Russell, Mark W., Geisler, Sarah S., Kearns, Samuel D., Karthik, Felix, Etheridge, Susan P., Monroe, Tanner O., Pottinger, Tess D., Kannankeril, Prince J., Shoemaker, M. Benjamin, Fountain, Darlene, Roden, Dan M., Faulkner, Meghan, MacLeod, Heather M., Burns, Kristin M., Yandell, Mark, Tristani-Firouzi, Martin, George, Jr., Alfred L., and McNally, Elizabeth M.

Published
2024
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45. The role of coronary artery disease in lung transplantation: a propensity-matched analysis

Author

Lüsebrink, Enzo, Gade, Nils, Seifert, Paula, Ceelen, Felix, Veit, Tobias, Fohrer, Fabian, Hoffmann, Sabine, Höpler, Julia, Binzenhöfer, Leonhard, Roden, Daniel, Saleh, Inas, Lanz, Hugo, Michel, Sebastian, Schneider, Christian, Irlbeck, Michael, Tomasi, Roland, Hatz, Rudolf, Hausleiter, Jörg, Hagl, Christian, Magnussen, Christina, Meder, Benjamin, Zimmer, Sebastian, Luedike, Peter, Schäfer, Andreas, Orban, Martin, Milger, Katrin, Behr, Jürgen, Massberg, Steffen, and Kneidinger, Nikolaus

Published
2024
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46. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Author

Suzuki, Ken, Hatzikotoulas, Konstantinos, Southam, Lorraine, Taylor, Henry J., Yin, Xianyong, Lorenz, Kim M., Mandla, Ravi, Huerta-Chagoya, Alicia, Melloni, Giorgio E. M., Kanoni, Stavroula, Rayner, Nigel W., Bocher, Ozvan, Arruda, Ana Luiza, Sonehara, Kyuto, Namba, Shinichi, Lee, Simon S. K., Preuss, Michael H., Petty, Lauren E., Schroeder, Philip, Vanderwerff, Brett, Kals, Mart, Bragg, Fiona, Lin, Kuang, Guo, Xiuqing, Zhang, Weihua, Yao, Jie, Kim, Young Jin, Graff, Mariaelisa, Takeuchi, Fumihiko, Nano, Jana, Lamri, Amel, Nakatochi, Masahiro, Moon, Sanghoon, Scott, Robert A., Cook, James P., Lee, Jung-Jin, Pan, Ian, Taliun, Daniel, Parra, Esteban J., Chai, Jin-Fang, Bielak, Lawrence F., Tabara, Yasuharu, Hai, Yang, Thorleifsson, Gudmar, Grarup, Niels, Sofer, Tamar, Wuttke, Matthias, Sarnowski, Chloé, Gieger, Christian, Nousome, Darryl, Trompet, Stella, Kwak, Soo-Heon, Long, Jirong, Sun, Meng, Tong, Lin, Chen, Wei-Min, Nongmaithem, Suraj S., Noordam, Raymond, Lim, Victor J. Y., Tam, Claudia H. T., Joo, Yoonjung Yoonie, Chen, Chien-Hsiun, Raffield, Laura M., Prins, Bram Peter, Nicolas, Aude, Yanek, Lisa R., Chen, Guanjie, Brody, Jennifer A., Kabagambe, Edmond, An, Ping, Xiang, Anny H., Choi, Hyeok Sun, Cade, Brian E., Tan, Jingyi, Broadaway, K. Alaine, Williamson, Alice, Kamali, Zoha, Cui, Jinrui, Thangam, Manonanthini, Adair, Linda S., Adeyemo, Adebowale, Aguilar-Salinas, Carlos A., Ahluwalia, Tarunveer S., Anand, Sonia S., Bertoni, Alain, Bork-Jensen, Jette, Brandslund, Ivan, Buchanan, Thomas A., Burant, Charles F., Butterworth, Adam S., Canouil, Mickaël, Chan, Juliana C. N., Chang, Li-Ching, Chee, Miao-Li, Chen, Ji, Chen, Shyh-Huei, Chen, Yuan-Tsong, Chen, Zhengming, Chuang, Lee-Ming, Cushman, Mary, Danesh, John, Das, Swapan K., de Silva, H. Janaka, Dedoussis, George, Dimitrov, Latchezar, Doumatey, Ayo P., Du, Shufa, Duan, Qing, Eckardt, Kai-Uwe, Emery, Leslie S., Evans, Daniel S., Evans, Michele K., Fischer, Krista, Floyd, James S., Ford, Ian, Franco, Oscar H., Frayling, Timothy M., Freedman, Barry I., Genter, Pauline, Gerstein, Hertzel C., Giedraitis, Vilmantas, González-Villalpando, Clicerio, González-Villalpando, Maria Elena, Gordon-Larsen, Penny, Gross, Myron, Guare, Lindsay A., Hackinger, Sophie, Hakaste, Liisa, Han, Sohee, Hattersley, Andrew T., Herder, Christian, Horikoshi, Momoko, Howard, Annie-Green, Hsueh, Willa, Huang, Mengna, Huang, Wei, Hung, Yi-Jen, Hwang, Mi Yeong, Hwu, Chii-Min, Ichihara, Sahoko, Ikram, Mohammad Arfan, Ingelsson, Martin, Islam, Md. Tariqul, Isono, Masato, Jang, Hye-Mi, Jasmine, Farzana, Jiang, Guozhi, Jonas, Jost B., Jørgensen, Torben, Kamanu, Frederick K., Kandeel, Fouad R., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kaur, Varinderpal, Kawaguchi, Takahisa, Keaton, Jacob M., Kho, Abel N., Khor, Chiea-Chuen, Kibriya, Muhammad G., Kim, Duk-Hwan, Kronenberg, Florian, Kuusisto, Johanna, Läll, Kristi, Lange, Leslie A., Lee, Kyung Min, Lee, Myung-Shik, Lee, Nanette R., Leong, Aaron, Li, Liming, Li, Yun, Li-Gao, Ruifang, Ligthart, Symen, Lindgren, Cecilia M., Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Locke, Adam E., Louie, Tin, Luan, Jian’an, Luk, Andrea O., Luo, Xi, Lv, Jun, Lynch, Julie A., Lyssenko, Valeriya, Maeda, Shiro, Mamakou, Vasiliki, Mansuri, Sohail Rafik, Matsuda, Koichi, Meitinger, Thomas, Melander, Olle, Metspalu, Andres, Mo, Huan, Morris, Andrew D., Moura, Filipe A., Nadler, Jerry L., Nalls, Michael A., Nayak, Uma, Ntalla, Ioanna, Okada, Yukinori, Orozco, Lorena, Patel, Sanjay R., Patil, Snehal, Pei, Pei, Pereira, Mark A., Peters, Annette, Pirie, Fraser J., Polikowsky, Hannah G., Porneala, Bianca, Prasad, Gauri, Rasmussen-Torvik, Laura J., Reiner, Alexander P., Roden, Michael, Rohde, Rebecca, Roll, Katheryn, Sabanayagam, Charumathi, Sandow, Kevin, Sankareswaran, Alagu, Sattar, Naveed, Schönherr, Sebastian, Shahriar, Mohammad, Shen, Botong, Shi, Jinxiu, Shin, Dong Mun, Shojima, Nobuhiro, Smith, Jennifer A., So, Wing Yee, Stančáková, Alena, Steinthorsdottir, Valgerdur, Stilp, Adrienne M., Strauch, Konstantin, Taylor, Kent D., Thorand, Barbara, Thorsteinsdottir, Unnur, Tomlinson, Brian, Tran, Tam C., Tsai, Fuu-Jen, Tuomilehto, Jaakko, Tusie-Luna, Teresa, Udler, Miriam S., Valladares-Salgado, Adan, van Dam, Rob M., van Klinken, Jan B., Varma, Rohit, Wacher-Rodarte, Niels, Wheeler, Eleanor, Wickremasinghe, Ananda R., van Dijk, Ko Willems, Witte, Daniel R., Yajnik, Chittaranjan S., Yamamoto, Ken, Yamamoto, Kenichi, Yoon, Kyungheon, Yu, Canqing, Yuan, Jian-Min, Yusuf, Salim, Zawistowski, Matthew, Zhang, Liang, Zheng, Wei, Raffel, Leslie J., Igase, Michiya, Ipp, Eli, Redline, Susan, Cho, Yoon Shin, Lind, Lars, Province, Michael A., Fornage, Myriam, Hanis, Craig L., Ingelsson, Erik, Zonderman, Alan B., Psaty, Bruce M., Wang, Ya-Xing, Rotimi, Charles N., Becker, Diane M., Matsuda, Fumihiko, Liu, Yongmei, Yokota, Mitsuhiro, Kardia, Sharon L. R., Peyser, Patricia A., Pankow, James S., Engert, James C., Bonnefond, Amélie, Froguel, Philippe, Wilson, James G., Sheu, Wayne H. H., Wu, Jer-Yuarn, Hayes, M. Geoffrey, Ma, Ronald C. W., Wong, Tien-Yin, Mook-Kanamori, Dennis O., Tuomi, Tiinamaija, Chandak, Giriraj R., Collins, Francis S., Bharadwaj, Dwaipayan, Paré, Guillaume, Sale, Michèle M., Ahsan, Habibul, Motala, Ayesha A., Shu, Xiao-Ou, Park, Kyong-Soo, Jukema, J. Wouter, Cruz, Miguel, Chen, Yii-Der Ida, Rich, Stephen S., McKean-Cowdin, Roberta, Grallert, Harald, Cheng, Ching-Yu, Ghanbari, Mohsen, Tai, E-Shyong, Dupuis, Josee, Kato, Norihiro, Laakso, Markku, Köttgen, Anna, Koh, Woon-Puay, Bowden, Donald W., Palmer, Colin N. A., Kooner, Jaspal S., Kooperberg, Charles, Liu, Simin, North, Kari E., Saleheen, Danish, Hansen, Torben, Pedersen, Oluf, Wareham, Nicholas J., Lee, Juyoung, Kim, Bong-Jo, Millwood, Iona Y., Walters, Robin G., Stefansson, Kari, Ahlqvist, Emma, Goodarzi, Mark O., Mohlke, Karen L., Langenberg, Claudia, Haiman, Christopher A., Loos, Ruth J. F., Florez, Jose C., Rader, Daniel J., Ritchie, Marylyn D., Zöllner, Sebastian, Mägi, Reedik, Marston, Nicholas A., Ruff, Christian T., van Heel, David A., Finer, Sarah, Denny, Joshua C., Yamauchi, Toshimasa, Kadowaki, Takashi, Chambers, John C., Ng, Maggie C. Y., Sim, Xueling, Below, Jennifer E., Tsao, Philip S., Chang, Kyong-Mi, McCarthy, Mark I., Meigs, James B., Mahajan, Anubha, Spracklen, Cassandra N., Mercader, Josep M., Boehnke, Michael, Rotter, Jerome I., Vujkovic, Marijana, Voight, Benjamin F., Morris, Andrew P., and Zeggini, Eleftheria

Published
2024
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49. Using a one-dimensional finite-element approximation of Webster's horn equation to estimate individual ear canal acoustic transfer from input impedances

Author

Wulbusch, Nick, Roden, Reinhild, Chernov, Alexey, and Blau, Matthias

Subjects
Mathematics - Optimization and Control, Electrical Engineering and Systems Science - Audio and Speech Processing, Mathematics - Numerical Analysis
Abstract

In many applications, knowledge of the sound pressure transfer to the eardrum is important. The transfer is highly influenced by the shape of the ear canal and its acoustic properties, such as the acoustic impedance at the eardrum. Invasive procedures to measure the sound pressure at the eardrum are usually elaborate or costly. In this work, we propose a numerical method to estimate the transfer impedance at the eardrum given only input impedance measurements at the ear canal entrance by using one-dimensional first-order finite elements and Nelder-Mead optimization algorithm. Estimations on the area function of the ear canal and the acoustic impedance at the eardrum are achieved. Results are validated through numerical simulations on ten different ear canal geometries and three different acoustic impedances at the eardrum using synthetically generated data from three-dimensional finite element simulations., Comment: 16 pages, 15 figures

Published
2023
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50. Detection of distant relatedness in biobanks to identify undiagnosed cases of Mendelian disease as applied to Long QT syndrome

Author

Megan C. Lancaster, Hung-Hsin Chen, M. Benjamin Shoemaker, Matthew R. Fleming, Teresa L. Strickland, James T. Baker, Grahame F. Evans, Hannah G. Polikowsky, David C. Samuels, Chad D. Huff, Dan M. Roden, and Jennifer E. Below

Subjects
Science
Abstract

Abstract Rare genetic diseases are typically studied in referral populations, resulting in underdiagnosis and biased assessment of penetrance and phenotype. To address this, we develop a generalizable method of genotype inference based on distant relatedness and deploy this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. We identify 9 LQT5 families referred to a single specialty clinic, each carrying p.Asp76Asn, the most common LQT5 variant. We uncover recent common ancestry and a single shared haplotype among probands. Application to a non-referral population of 69,819 BioVU biobank subjects identifies 22 additional subjects sharing this haplotype, which we confirm to carry p.Asp76Asn. Referral and non-referral carriers have prolonged QT interval corrected for heart rate (QTc) compared to controls, and, among carriers, the QTc polygenic score is independently associated with QTc prolongation. Thus, our innovative analysis of shared chromosomal segments identifies undiagnosed cases of genetic disease and refines the understanding of LQT5 penetrance and phenotype.

Published
2024
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