Digital Commons Network^™

Fusionai, A Dna-Sequence-Based Deep Learning Protocol Reduces The False Positives Of Human Fusion Gene Prediction, Pora Kim, Hua Tan, Jiajia Liu, Himansu Kumar, Xiaobo Zhou

Faculty, Staff and Student Publications

Even though there were many tool developments of fusion gene prediction from NGS data, too many false positives are still an issue. Wise use of the genomic features around the fusion gene breakpoints will be helpful to identify reliable fusion genes efficiently. For this aim, we developed FusionAI, a deep learning pipeline predicting human fusion gene breakpoints from DNA sequence. FusionAI is freely available via https://compbio.uth.edu/FusionGDB2/FusionAI. For complete details on the use and execution of this protocol, please refer to Kim et al. (2021b).

Proteomic Profiling Based Classification Of Cll Provides Prognostication For Modern Therapy And Identifies Novel Therapeutic Targets, Ti'ara L Griffen, Fieke W Hoff, Yihua Qiu, James W Lillard, Alessandra Ferrajoli, Philip Thompson, Endurance Toro, Kevin Ruiz, Jan Burger, William Wierda, Steven M Kornblau

Faculty, Staff and Student Publications

Protein expression for 384 total and post-translationally modified proteins was assessed in 871 CLL and MSBL patients and was integrated with clinical data to identify strategies for improving diagnostics and therapy, making this the largest CLL proteomics study to date. Proteomics identified six recurrent signatures that were highly prognostic of survival and time to first or second treatment at three levels: individual proteins, when grouped into 40 functionally related groups (PFGs), and systemically in signatures (SGs). A novel SG characterized by hairy cell leukemia like proteomics but poor therapy response was discovered. SG membership superseded other prognostic factors (Rai Staging, …

Predicting Health-Related Social Needs In Medicaid And Medicare Populations Using Machine Learning, Jennifer Holcomb, Luis C Oliveira, Linda Highfield, Kevin O Hwang, Luca Giancardo, Elmer Victor Bernstam

Faculty, Staff and Student Publications

Providers currently rely on universal screening to identify health-related social needs (HRSNs). Predicting HRSNs using EHR and community-level data could be more efficient and less resource intensive. Using machine learning models, we evaluated the predictive performance of HRSN status from EHR and community-level social determinants of health (SDOH) data for Medicare and Medicaid beneficiaries participating in the Accountable Health Communities Model. We hypothesized that Medicaid insurance coverage would predict HRSN status. All models significantly outperformed the baseline Medicaid hypothesis. AUCs ranged from 0.59 to 0.68. The top performance (AUC = 0.68 CI 0.66-0.70) was achieved by the "any HRSNs" outcome, …

Bigmouth: Development And Maintenance Of A Successful Dental Data Repository, Muhammad F Walji, Heiko Spallek, Krishna Kumar Kookal, Jane Barrow, Britta Magnuson, Tamanna Tiwari, Udochukwu Oyoyo, Michael Brandt, Brian J Howe, Gary C Anderson, Joel M White, Elsbeth Kalenderian

Faculty, Staff and Student Publications

Few clinical datasets exist in dentistry to conduct secondary research. Hence, a novel dental data repository called BigMouth was developed, which has grown to include 11 academic institutions contributing Electronic Health Record data on over 4.5 million patients. The primary purpose for BigMouth is to serve as a high-quality resource for rapidly conducting oral health-related research. BigMouth allows for assessing the oral health status of a diverse US patient population; provides rationale and evidence for new oral health care delivery modes; and embraces the specific oral health research education mission. A data governance framework that encouraged data sharing while controlling …

Durable Reduction Of Clostridioides Difficile Infection Recurrence And Microbiome Restoration After Treatment With Rbx2660: Results From An Open-Label Phase 2 Clinical Trial, Robert Orenstein, Erik R Dubberke, Sahil Khanna, Christine H Lee, David Yoho, Stuart Johnson, Gail Hecht, Herbert L Dupont, Dale N Gerding, Ken F Blount, Sarah Mische, Adam Harvey

Faculty, Staff and Student Publications

BACKGROUND: Effective treatment options for recurrent Clostridioides difficile infection (rCDI) are limited, with high recurrence rates associated with the current standard of care. Herein we report results from an open-label Phase 2 trial to evaluate the safety, efficacy, and durability of RBX2660-a standardized microbiota-based investigational live biotherapeutic-and a closely-matched historical control cohort.

METHODS: This prospective, multicenter, open-label Phase 2 study enrolled patients who had experienced either ≥ 2 recurrences of CDI, treated by standard-of-care antibiotic therapy, after a primary CDI episode, or ≥ 2 episodes of severe CDI requiring hospitalization. Participants received up to 2 doses of RBX2660 rectally administered …

Synergy Of Venetoclax And 8-Chloro-Adenosine In Aml: The Interplay Of Rrna Inhibition And Fatty Acid Metabolism, Dinh Hoa Hoang, Corey Morales, Ivan Rodriguez Rodriguez, Melissa Valerio, Jiamin Guo, Min-Hsuan Chen, Xiwei Wu, David Horne, Varsha Gandhi, Lisa S Chen, Bin Zhang, Vinod Pullarkat, Steven T Rosen, Guido Marcucci, Ralf Buettner, Le Xuan Truong Nguyen

Faculty, Staff and Student Publications

It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado …

A Novel Proton-Integrating Radiography System Design Using A Monolithic Scintillator Detector: Experimental Studies, Chinmay D Darne, Daniel G Robertson, Fahed Alsanea, Charles-Antoine Collins-Fekete, Sam Beddar

Faculty, Staff and Student Publications

Research on proton-based imaging systems aims to improve treatment planning, internal anatomy visualization, and patient alignment for proton radiotherapy. The purpose of this study was to demonstrate a new proton radiography system design consisting of a monolithic plastic scintillator volume and two optical cameras for use with scanning proton pencil beams. Unlike the thin scintillating plates currently used for proton radiography, the plastic scintillator volume (20 × 20 × 20 cm

Blood-Based Biomarker Panel For Personalized Lung Cancer Risk Assessment, Johannes F Fahrmann, Tracey Marsh, Ehsan Irajizad, Nikul Patel, Eunice Murage, Jody Vykoukal, Jennifer B Dennison, Kim-Anh Do, Edwin Ostrin, Margaret R Spitz, Stephen Lam, Sanjay Shete, Rafael Meza, Martin C Tammemägi, Ziding Feng, Samir M Hanash

Faculty, Staff and Student Publications

Purpose: To investigate whether a panel of circulating protein biomarkers would improve risk assessment for lung cancer screening in combination with a risk model on the basis of participant characteristics.

Methods: A blinded validation study was performed using prostate lung colorectal ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the performance of a four-marker protein panel (4MP) consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in combination with a lung cancer risk prediction model (PLCOm2012) compared with current US Preventive Services Task Force (USPSTF) screening criteria. The 4MP was …

Measurable Residual Disease Response And Prognosis In Treatment-Naïve Acute Myeloid Leukemia With Venetoclax And Azacitidine, Keith W Pratz, Brian A Jonas, Vinod Pullarkat, Christian Recher, Andre C Schuh, Michael J Thirman, Jacqueline S Garcia, Courtney D Dinardo, Vladimir Vorobyev, Nicola S Fracchiolla, Su-Peng Yeh, Jun Ho Jang, Muhit Ozcan, Kazuhito Yamamoto, Arpad Illes, Ying Zhou, Monique Dail, Brenda Chyla, Jalaja Potluri, Hartmut Döhner

Faculty, Staff and Student Publications

PURPOSE: There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10

METHODS: The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10

RESULTS: One hundred …

Elucidating Mechanisms Of Genetic Cross-Disease Associations At The Procr Vascular Disease Locus, David Stacey, Lingyan Chen, Paulina J Stanczyk, Joanna M M Howson, Amy M Mason, Stephen Burgess, Stephen Macdonald, Jonathan Langdown, Harriett Mckinney, Kate Downes, Neda Farahi, James E Peters, Saonli Basu, James S Pankow, Weihong Tang, Nathan Pankratz, Maria Sabater-Lleal, Paul S De Vries, Nicholas L Smith, Amy D Gelinas, Daniel J Schneider, Nebojsa Janjic, Nilesh J Samani, Shu Ye, Charlotte Summers, Edwin R Chilvers, John Danesh, Dirk S Paul

Faculty, Staff and Student Publications

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, …

Analysis Of The Circrna And T-Ucr Populations Identifies Convergent Pathways In Mouse And Human Models Of Rett Syndrome, Edilene Siqueira, Aida Obiols-Guardia, Olga C Jorge-Torres, Cristina Oliveira-Mateos, Marta Soler, Deepthi Ramesh-Kumar, Fernando Setién, Daniëlle Van Rossum, Ainhoa Pascual-Alonso, Clara Xiol, Cristina Ivan, Masayoshi Shimizu, Judith Armstrong, George A Calin, R Jeroen Pasterkamp, Manel Esteller, Sonia Guil

Faculty, Staff and Student Publications

Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key …

Using Implementation Mapping To Develop And Test An Implementation Strategy For Active Learning To Promote Physical Activity In Children: A Feasibility Study Using A Hybrid Type 2 Design, Timothy J Walker, Harold W Kohl, John B Bartholomew, Charles Green, Maria E Fernández

Faculty, Staff and Student Publications

BACKGROUND: Incorporating physical movement in the teaching of academic content (active learning) is a promising approach to improve children's health and academic performance. Despite documented benefits, implementation of active learning remains challenging for schools. The aims of this study are to develop an implementation strategy to support the delivery of active learning in elementary schools and examine the impact of the developed implementation strategy on the implementation and effectiveness of active learning.

METHODS: Aim 1 will use Implementation Mapping, which is a multi-step approach that guides the use of theory, stakeholder input, and existing literature to develop a scientifically based …

Chromosomal Imbalances Detected Via Rna-Sequencing In 28 Cancers, Zuhal Ozcan, Francis A San Lucas, Justin W Wong, Kyle Chang, Konrad H Stopsack, Jerry Fowler, Yasminka A Jakubek, Paul Scheet

Faculty, Staff and Student Publications

Motivation: RNA-sequencing (RNA-seq) of tumor tissue is typically only used to measure gene expression. Here, we present a statistical approach that leverages existing RNA-seq data to also detect somatic copy number alterations (SCNAs), a pervasive phenomenon in human cancers, without a need to sequence the corresponding DNA.

Results: We present an analysis of 4942 participant samples from 28 cancers in The Cancer Genome Atlas (TCGA), demonstrating robust detection of SCNAs from RNA-seq. Using genotype imputation and haplotype information, our RNA-based method had a median sensitivity of 85% to detect SCNAs defined by DNA analysis, at high specificity (∼95%). As an …

Prognostic Impact Of High Baseline Stromal Tumor-Infiltrating Lymphocytes In The Absence Of Pathologic Complete Response In Early-Stage Triple-Negative Breast Cancer, Nour Abuhadra, Ryan Sun, Jennifer K Litton, Gaiane M Rauch, Clinton Yam, Jeffrey T Chang, Sahil Seth, Roland Bassett, Bora Lim, Alastair M Thompson, Elizabeth Mittendorf, Beatriz E Adrada, Senthil Damodaran, Jason White, Elizabeth Ravenberg, Rosalind Candelaria, Banu Arun, Naoto T Ueno, Lumarie Santiago, Sadia Saleem, Sausan Abouharb, Rashmi K Murthy, Nuhad Ibrahim, Aysegul A Sahin, Vicente Valero, William Fraser Symmans, Debu Tripathy, Stacy Moulder, Lei Huo

Faculty, Staff and Student Publications

High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR after neoadjuvant chemotherapy (NACT). In this prospective NACT study, pretreatment biopsies from 318 patients with early-stage TNBC were evaluated for sTILs. Recursive partitioning analysis (RPA) was applied to search for the sTIL cutoff best associated with a pCR. With ≥20% sTILs identified as the optimal cutoff, 33% patients had high sTILs (pCR rate 64%) and 67% had low sTILs (pCR rate …

The Impact Of Radiation Dose To Heart Substructures On Major Coronary Events And Patient Survival After Chemoradiation Therapy For Esophageal Cancer, Xin Wang, Nicolas L Palaskas, Brian P Hobbs, Jun-Ichi Abe, Kevin T Nead, Syed Wamique Yusuf, Joerg Hermann, Anita Deswal, Steven H Lin

Faculty, Staff and Student Publications

Simple Summary

Whether it is necessary to evaluate the radiation exposure of cardiac substructures when making radiotherapy plans is one of the current research hotspots. In this cohort study of 355 patients with esophageal cancer, the radiation dose to key coronary substructures such as the left anterior descending artery V30_Gy and mean left main coronary artery was closely associated with major coronary events and overall patient survival, and showed better predictive value than the mean heart dose or heart V30_Gy recommended by current guidelines. Our findings suggest that, in addition to the whole heart, key coronary substructures should …

Identification Of A Novel Microdeletion Causative Of Nance-Horan Syndrome, Mariana Lopez Martinolich, Hope Northrup, Pedro Mancias, Paul Hillman, Kavya Rao, Kate Mowrey

Faculty, Staff and Student Publications

BACKGROUND: Nance-Horan syndrome (NHS) is a rare X-linked genetic disorder characterized by ophthalmologic and dental anomalies as well as dysmorphic facies. The clinical phenotype in males includes congenital cataracts, vision loss, microcornea, nystagmus, microphthalmia, glaucoma, screwdriver blade-shaped incisors, supernumerary maxillary incisors, diastema, delays, intellectual disability, and dysmorphic facies. With the evolution of array-CGH technology, a total of five kindreds with NHS have been reported in the medical literature with microdeletions encompassing the NHS gene rather than sequencing variants.

METHODS: The patient is a 19-year-old male born to non-consanguineous parents with a past medical history of bilateral congenital cataracts, nystagmus, poor …

The Clock Modulator Nobiletin Mitigates Astrogliosis-Associated Neuroinflammation And Disease Hallmarks In An Alzheimer’S Disease Model, Marvin Wirianto, Chih-Yen Wang, Eunju Kim, Nobuya Koike, Ruben Gomez-Gutierrez, Kazunari Nohara, Gabriel Escobedo, Jong Min Choi, Chorong Han, Kazuhiro Yagita, Sung Yun Jung, Claudio Soto, Hyun Kyoung Lee, Rodrigo Morales, Seung-Hee Yoo, Zheng Chen

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a devastating neurodegenerative disorder, and there is a pressing need to identify disease-modifying factors and devise interventional strategies. The circadian clock, our intrinsic biological timer, orchestrates various cellular and physiological processes including gene expression, sleep, and neuroinflammation; conversely, circadian dysfunctions are closely associated with and/or contribute to AD hallmarks. We previously reported that the natural compound Nobiletin (NOB) is a clock-enhancing modulator that promotes physiological health and healthy aging. In the current study, we treated the double transgenic AD model mice, APP/PS1, with NOB-containing diets. NOB significantly alleviated β-amyloid burden in both the hippocampus and the …

Use Of The Deep Learning Approach To Measure Alveolar Bone Level, Chun-Teh Lee, Tanjida Kabir, Jiman Nelson, Sally Sheng, Hsiu-Wan Meng, Thomas E Van Dyke, Muhammad F Walji, Xiaoqian Jiang, Shayan Shams

Faculty, Staff and Student Publications

AIM: The goal was to use a deep convolutional neural network to measure the radiographic alveolar bone level to aid periodontal diagnosis.

MATERIALS AND METHODS: A deep learning (DL) model was developed by integrating three segmentation networks (bone area, tooth, cemento-enamel junction) and image analysis to measure the radiographic bone level and assign radiographic bone loss (RBL) stages. The percentage of RBL was calculated to determine the stage of RBL for each tooth. A provisional periodontal diagnosis was assigned using the 2018 periodontitis classification. RBL percentage, staging, and presumptive diagnosis were compared with the measurements and diagnoses made by the …

Reporting Outcomes Of Pediatric Intensive Care Unit Patients To Referring Physicians Via An Electronic Health Record-Based Feedback System, Christina L Cifra, Cody R Tigges, Sarah L Miller, Nathaniel Curl, Christopher D Monson, Kimberly C Dukes, Heather S Reisinger, Priyadarshini R Pennathur, Dean F Sittig, Hardeep Singh

Faculty, Staff and Student Publications

BACKGROUND: Many critically ill children are initially evaluated in front-line settings by clinicians with variable pediatric training before they are transferred to a pediatric intensive care unit (PICU). Because clinicians learn from past performance, communicating outcomes of patients back to front-line clinicians who provide pediatric emergency care could be valuable; however, referring clinicians do not consistently receive this important feedback.

OBJECTIVES: Our aim was to determine the feasibility, usability, and clinical relevance of a semiautomated electronic health record (EHR)-supported system developed at a single institution to deliver timely and relevant PICU patient outcome feedback to referring emergency department (ED) physicians. …

Counterfactual Analysis Of Differential Comorbidity Risk Factors In Alzheimer’S Disease And Related Dementias, Yejin Kim, Kai Zhang, Sean I Savitz, Luyao Chen, Paul E Schulz, Xiaoqian Jiang

Faculty, Staff and Student Publications

Alzheimer’s disease and related dementias (ADRD) is a multifactorial disease that involves several different etiologic mechanisms with various comorbidities. There is also significant heterogeneity in the prevalence of ADRD across diverse demographics groups. Association studies on such heterogeneous comorbidity risk factors are limited in their ability to determine causation. We aim to compare counterfactual treatment effects of various comorbidity in ADRD in different racial groups (African Americans and Caucasians). We used 138,026 ADRD and 1:1 matched older adults without ADRD from nationwide electronic health records, which extensively cover a large population’s long medical history in breadth. We matched African Americans …

Clinical Outcomes And Bacterial Characteristics Of Carbapenem-Resistant Klebsiella Pneumoniae Complex Among Patients From Different Global Regions (Crackle-2): A Prospective, Multicentre, Cohort Study, Minggui Wang, Michelle Earley, Liang Chen, Blake M Hanson, Yunsong Yu, Zhengyin Liu, Soraya Salcedo, Eric Cober, Lanjuan Li, Souha S Kanj, Hainv Gao, Jose M Munita, Karen Ordoñez, Greg Weston, Michael J Satlin, Sandra L Valderrama-Beltrán, Kalisvar Marimuthu, Martin E Stryjewski, Lauren Komarow, Courtney Luterbach, Steve H Marshall, Susan D Rudin, Claudia Manca, David L Paterson, Jinnethe Reyes, Maria V Villegas, Scott Evans, Carol Hill, Rebekka Arias, Keri Baum, Bettina C Fries, Yohei Doi, Robin Patel, Barry N Kreiswirth, Robert A Bonomo, Henry F Chambers, Vance G Fowler, Cesar A Arias, David Van Duin, Multi-Drug Resistant Organism Network Investigators

Faculty, Staff and Student Publications

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries.

METHODS: In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability …

Clonal Hematopoiesis Is Associated With Higher Risk Of Stroke, Romit Bhattacharya, Seyedeh M Zekavat, Jeffrey Haessler, Myriam Fornage, Laura Raffield, Md Mesbah Uddin, Alexander G Bick, Abhishek Niroula, Bing Yu, Christopher Gibson, Gabriel Griffin, Alanna C Morrison, Bruce M Psaty, William T Longstreth, Joshua C Bis, Stephen S Rich, Jerome I Rotter, Russell P Tracy, Adolfo Correa, Sudha Seshadri, Andrew Johnson, Jason M Collins, Kathleen M Hayden, Tracy E Madsen, Christie M Ballantyne, Siddhartha Jaiswal, Benjamin L Ebert, Charles Kooperberg, Joann E Manson, Eric A Whitsel, Nhlbi Trans-Omics For Precision Medicine Program, Pradeep Natarajan, Alexander P Reiner

Faculty, Staff and Student Publications

Background and purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.

Methods: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association …

Fungi: Friend Or Foe? A Mycobiome Evaluation In Children With Autism And Gastrointestinal Symptoms, Jane Alookaran, Yuying Liu, Thomas A Auchtung, Amirali Tahanan, Manouchehr Hessabi, Parisa Asgarisabet, Mohammad H Rahbar, Nicole Y Fatheree, Deborah A Pearson, Rosleen Mansour, Melissa R Van Arsdall, Fernando Navarro, J Marc Rhoads

Faculty, Staff and Student Publications

Gastrointestinal (GI) symptoms often affect children with autism spectrum disorders (ASD) and GI symptoms have been associated with an abnormal fecal microbiome. There is limited evidence of Candida species being more prevalent in children with ASD. We enrolled 20 children with ASD and GI symptoms (ASD + GI), 10 children with ASD but no GI symptoms (ASD - GI), and 20 from typically developing (TD) children in this pilot study. Fecal mycobiome taxa were analyzed by Internal Transcribed Spacer sequencing. GI symptoms (GI Severity Index [GSI]), behavioral symptoms (Social Responsiveness Scale -2 [SRS-2]), inflammation and fungal immunity (fecal calprotectin and …

Assessing The Contribution Of Rare Variants To Complex Trait Heritability From Whole-Genome Sequence Data, Pierrick Wainschtein, Deepti Jain, Zhili Zheng, Topmed Anthropometry Working Group, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, L Adrienne Cupples, Aladdin H Shadyab, Barbara Mcknight, Benjamin M Shoemaker, Braxton D Mitchell, Bruce M Psaty, Charles Kooperberg, Ching-Ti Liu, Christine M Albert, Dan Roden, Daniel I Chasman, Dawood Darbar, Donald M Lloyd-Jones, Donna K Arnett, Elizabeth A Regan, Eric Boerwinkle, Jerome I Rotter, Jeffrey R O'Connell, Lisa R Yanek, Mariza De Andrade, Matthew A Allison, Merry-Lynn N Mcdonald, Mina K Chung, Myriam Fornage, Nathalie Chami, Nicholas L Smith, Patrick T Ellinor, Ramachandran S Vasan, Rasika A Mathias, Ruth J F Loos, Stephen S Rich, Steven A Lubitz, Susan R Heckbert, Susan Redline, Xiuqing Guo, Y -D Ida Chen, Cecelia A Laurie, Ryan D Hernandez, Stephen T Mcgarvey, Michael E Goddard, Cathy C Laurie, Kari E North, Leslie A Lange, Bruce S Weir, Loic Yengo, Jian Yang, Peter M Visscher

Faculty, Staff and Student Publications

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error …

Community-Clinic Linkages For Promoting Hiv Prevention: Organizational Networks For Prep Client Referrals And Collaborations, Rebecca L Mauldin, Tamara Al Rawwad, Muhammad Amith, Lisa M Kuhns, John A Schneider, Kayo Fujimoto

Faculty, Staff and Student Publications

Community-clinic linkages may help communities increase HIV pre-exposure prophylaxis (PrEP) uptake. Referrals from community-based organizations may be particularly important for linking Black men who have sex with men (MSM) to PrEP. This study describes PrEP referral and HIV/STI prevention networks among organizations that serve MSM in Houston, TX (N = 40), and Chicago, IL (N = 28), and compares network positions of organizations based on percentage of Black/African American clients. A majority of organizations conducted PrEP awareness/promotion activities, but fewer made PrEP referrals, with little overlap between the collaboration and referral networks. The networks tended to have a …

Type 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes In 454,193 Individuals Across 13 Cohorts, Daniel Dicorpo, Jessica Leclair, Joanne B Cole, Chloé Sarnowski, Fariba Ahmadizar, Lawrence F Bielak, Anneke Blokstra, Erwin P Bottinger, Layal Chaker, Yii-Der I Chen, Ye Chen, Paul S De Vries, Tariq Faquih, Mohsen Ghanbari, Valborg Gudmundsdottir, Xiuqing Guo, Natalie R Hasbani, Dorina Ibi, M Arfan Ikram, Maryam Kavousi, Hampton L Leonard, Aaron Leong, Josep M Mercader, Alanna C Morrison, Girish N Nadkarni, Mike A Nalls, Raymond Noordam, Michael Preuss, Jennifer A Smith, Stella Trompet, Petra Vissink, Jie Yao, Wei Zhao, Eric Boerwinkle, Mark O Goodarzi, Vilmundur Gudnason, J Wouter Jukema, Sharon L R Kardia, Ruth J F Loos, Ching-Ti Liu, Alisa K Manning, Dennis Mook-Kanamori, James S Pankow, H Susan J Picavet, Naveed Sattar, Eleanor M Simonsick, W M Monique Verschuren, Ko Willems Van Dijk, Jose C Florez, Jerome I Rotter, James B Meigs, Josée Dupuis, Miriam S Udler

Faculty, Staff and Student Publications

OBJECTIVE: Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed.

RESEARCH DESIGN AND METHODS: Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) …

Cancer Incidence, Mortality, Years Of Life Lost, Years Lived With Disability, And Disability-Adjusted Life Years For 29 Cancer Groups From 2010 To 2019: A Systematic Analysis For The Global Burden Of Disease Study 2019, Jonathan M Kocarnik, Kelly Compton, Frances E Dean, Weijia Fu, Brian L Gaw, James D Harvey, Hannah Jacqueline Henrikson, Dan Lu, Alyssa Pennini, Rixing Xu, Emad Ababneh, Mohsen Abbasi-Kangevari, Hedayat Abbastabar, Sherief M Abd-Elsalam, Amir Abdoli, Aidin Abedi, Hassan Abidi, Hassan Abolhassani, Isaac Akinkunmi Adedeji, Qorinah Estiningtyas Sakilah Adnani, Shailesh M Advani, Muhammad Sohail Afzal, Mohammad Aghaali, Bright Opoku Ahinkorah, Sajjad Ahmad, Tauseef Ahmad, Ali Ahmadi, Sepideh Ahmadi, Tarik Ahmed Rashid, Yusra Ahmed Salih, Gizachew Taddesse Akalu, Addis Aklilu, Tayyaba Akram, Chisom Joyqueenet Akunna, Hanadi Al Hamad, Fares Alahdab, Ziyad Al-Aly, Saqib Ali, Yousef Alimohamadi, Vahid Alipour, Syed Mohamed Aljunid, Motasem Alkhayyat, Amir Almasi-Hashiani, Nihad A Almasri, Sadeq Ali Ali Al-Maweri, Sami Almustanyir, Nivaldo Alonso, Nelson Alvis-Guzman, Hubert Amu, Etsay Woldu Anbesu, Robert Ancuceanu, Fereshteh Ansari, Alireza Ansari-Moghaddam, Maxwell Hubert Antwi, Davood Anvari, Anayochukwu Edward Anyasodor, Muhammad Aqeel, Jalal Arabloo, Morteza Arab-Zozani, Olatunde Aremu, Hany Ariffin, Timur Aripov, Muhammad Arshad, Al Artaman, Judie Arulappan, Zatollah Asemi, Mohammad Asghari Jafarabadi, Tahira Ashraf, Prince Atorkey, Avinash Aujayeb, Marcel Ausloos, Atalel Fentahun Awedew, Beatriz Paulina Ayala Quintanilla, Temesgen Ayenew, Mohammed A Azab, Sina Azadnajafabad, Amirhossein Azari Jafari, Ghasem Azarian, Ahmed Y Azzam, Ashish D Badiye, Saeed Bahadory, Atif Amin Baig, Jennifer L Baker, Senthilkumar Balakrishnan, Maciej Banach, Till Winfried Bärnighausen, Francesco Barone-Adesi, Fabio Barra, Amadou Barrow, Masoud Behzadifar, Uzma Iqbal Belgaumi, Woldesellassie M Mequanint Bezabhe, Yihienew Mequanint Bezabih, Devidas S Bhagat, Akshaya Srikanth Bhagavathula, Nikha Bhardwaj, Pankaj Bhardwaj, Sonu Bhaskar, Krittika Bhattacharyya, Vijayalakshmi S Bhojaraja, Sadia Bibi, Ali Bijani, Antonio Biondi, Catherine Bisignano, Tone Bjørge, Archie Bleyer, Oleg Blyuss, Obasanjo Afolabi Bolarinwa, Srinivasa Rao Bolla, Dejana Braithwaite, Amanpreet Brar, Hermann Brenner, Maria Teresa Bustamante-Teixeira, Nadeem Shafique Butt, Zahid A Butt, Florentino Luciano Caetano Dos Santos, Yin Cao, Giulia Carreras, Ferrán Catalá-López, Francieli Cembranel, Ester Cerin, Achille Cernigliaro, Raja Chandra Chakinala, Soosanna Kumary Chattu, Vijay Kumar Chattu, Pankaj Chaturvedi, Odgerel Chimed-Ochir, Daniel Youngwhan Cho, Devasahayam J Christopher, Dinh-Toi Chu, Michael T Chung, Joao Conde, Sanda Cortés, Paolo Angelo Cortesi, Vera Marisa Costa, Amanda Ramos Cunha, Omid Dadras, Amare Belachew Dagnew, Saad M A Dahlawi, Xiaochen Dai, Lalit Dandona, Rakhi Dandona, Aso Mohammad Darwesh, José Das Neves, Fernando Pio De La Hoz, Asmamaw Bizuneh Demis, Edgar Denova-Gutiérrez, Deepak Dhamnetiya, Mandira Lamichhane Dhimal, Meghnath Dhimal, Mostafa Dianatinasab, Daniel Diaz, Shirin Djalalinia, Huyen Phuc Do, Saeid Doaei, Fariba Dorostkar, Francisco Winter Dos Santos Figueiredo, Tim Robert Driscoll, Hedyeh Ebrahimi, Sahar Eftekharzadeh, Maha El Tantawi, Hassan El-Abid, Iffat Elbarazi, Hala Rashad Elhabashy, Muhammed Elhadi, Shaimaa I El-Jaafary, Babak Eshrati, Sharareh Eskandarieh, Firooz Esmaeilzadeh, Arash Etemadi, Sayeh Ezzikouri, Mohammed Faisaluddin, Emerito Jose A Faraon, Jawad Fares, Farshad Farzadfar, Abdullah Hamid Feroze, Simone Ferrero, Lorenzo Ferro Desideri, Irina Filip, Florian Fischer, James L Fisher, Masoud Foroutan, Takeshi Fukumoto, Peter Andras Gaal, Mohamed M Gad, Muktar A Gadanya, Silvano Gallus, Mariana Gaspar Fonseca, Abera Getachew Obsa, Mansour Ghafourifard, Ahmad Ghashghaee, Nermin Ghith, Maryam Gholamalizadeh, Syed Amir Gilani, Themba G Ginindza, Abraham Tamirat T Gizaw, James C Glasbey, Mahaveer Golechha, Pouya Goleij, Ricardo Santiago Gomez, Sameer Vali Gopalani, Giuseppe Gorini, Houman Goudarzi, Giuseppe Grosso, Mohammed Ibrahim Mohialdeen Gubari, Maximiliano Ribeiro Guerra, Avirup Guha, D Sanjeeva Gunasekera, Bhawna Gupta, Veer Bala Gupta, Vivek Kumar Gupta, Reyna Alma Gutiérrez, Nima Hafezi-Nejad, Mohammad Rifat Haider, Arvin Haj-Mirzaian, Rabih Halwani, Randah R Hamadeh, Sajid Hameed, Samer Hamidi, Asif Hanif, Shafiul Haque, Netanja I Harlianto, Josep Maria Haro, Ahmed I Hasaballah, Soheil Hassanipour, Roderick J Hay, Simon I Hay, Khezar Hayat, Golnaz Heidari, Mohammad Heidari, Brenda Yuliana Herrera-Serna, Claudiu Herteliu, Kamal Hezam, Ramesh Holla, Md Mahbub Hossain, Mohammad Bellal Hossain Hossain, Mohammad-Salar Hosseini, Mostafa Hosseini, Mehdi Hosseinzadeh, Mihaela Hostiuc, Sorin Hostiuc, Mowafa Househ, Mohamed Hsairi, Junjie Huang, Fernando N Hugo, Rabia Hussain, Nawfal R Hussein, Bing-Fang Hwang, Ivo Iavicoli, Segun Emmanuel Ibitoye, Fidelia Ida, Kevin S Ikuta, Olayinka Stephen Ilesanmi, Irena M Ilic, Milena D Ilic, Lalu Muhammad Irham, Jessica Y Islam, Rakibul M Islam, Sheikh Mohammed Shariful Islam, Nahlah Elkudssiah Ismail, Gaetano Isola, Masao Iwagami, Louis Jacob, Vardhmaan Jain, Mihajlo B Jakovljevic, Tahereh Javaheri, Shubha Jayaram, Seyed Behzad Jazayeri, Ravi Prakash Jha, Jost B Jonas, Tamas Joo, Nitin Joseph, Farahnaz Joukar, Mikk Jürisson, Ali Kabir, Danial Kahrizi, Leila R Kalankesh, Rohollah Kalhor, Feroze Kaliyadan, Yogeshwar Kalkonde, Ashwin Kamath, Nawzad Kameran Al-Salihi, Himal Kandel, Neeti Kapoor, André Karch, Ayele Semachew Kasa, Srinivasa Vittal Katikireddi, Joonas H Kauppila, Taras Kavetskyy, Sewnet Adem Kebede, Pedram Keshavarz, Mohammad Keykhaei, Yousef Saleh Khader, Rovshan Khalilov, Gulfaraz Khan, Maseer Khan, Md Nuruzzaman Khan, Moien A B Khan, Young-Ho Khang, Amir M Khater, Maryam Khayamzadeh, Gyu Ri Kim, Yun Jin Kim, Adnan Kisa, Sezer Kisa, Katarzyna Kissimova-Skarbek, Jacek A Kopec, Rajasekaran Koteeswaran, Parvaiz A Koul, Sindhura Lakshmi Koulmane Laxminarayana, Ai Koyanagi, Burcu Kucuk Bicer, Nuworza Kugbey, G Anil Kumar, Narinder Kumar, Nithin Kumar, Om P Kurmi, Tezer Kutluk, Carlo La Vecchia, Faris Hasan Lami, Iván Landires, Paolo Lauriola, Sang-Woong Lee, Shaun Wen Huey Lee, Wei-Chen Lee, Yo Han Lee, James Leigh, Elvynna Leong, Jiarui Li, Ming-Chieh Li, Xuefeng Liu, Joana A Loureiro, Raimundas Lunevicius, Muhammed Magdy Abd El Razek, Azeem Majeed, Alaa Makki, Shilpa Male, Ahmad Azam Malik, Mohammad Ali Mansournia, Santi Martini, Seyedeh Zahra Masoumi, Prashant Mathur, Martin Mckee, Ravi Mehrotra, Walter Mendoza, Ritesh G Menezes, Endalkachew Worku Mengesha, Mohamed Kamal Mesregah, Tomislav Mestrovic, Junmei Miao Jonasson, Bartosz Miazgowski, Tomasz Miazgowski, Irmina Maria Michalek, Ted R Miller, Hamed Mirzaei, Hamid Reza Mirzaei, Sanjeev Misra, Prasanna Mithra, Masoud Moghadaszadeh, Karzan Abdulmuhsin Mohammad, Yousef Mohammad, Mokhtar Mohammadi, Seyyede Momeneh Mohammadi, Abdollah Mohammadian-Hafshejani, Shafiu Mohammed, Nagabhishek Moka, Ali H Mokdad, Mariam Molokhia, Lorenzo Monasta, Mohammad Ali Moni, Mohammad Amin Moosavi, Yousef Moradi, Paula Moraga, Joana Morgado-Da-Costa, Shane Douglas Morrison, Abbas Mosapour, Sumaira Mubarik, Lillian Mwanri, Ahamarshan Jayaraman Nagarajan, Shankar Prasad Nagaraju, Chie Nagata, Mukhammad David Naimzada, Vinay Nangia, Atta Abbas Naqvi, Sreenivas Narasimha Swamy, Rawlance Ndejjo, Sabina O Nduaguba, Ionut Negoi, Serban Mircea Negru, Sandhya Neupane Kandel, Cuong Tat Nguyen, Huong Lan Thi Nguyen, Robina Khan Niazi, Chukwudi A Nnaji, Nurulamin M Noor, Virginia Nuñez-Samudio, Chimezie Igwegbe Nzoputam, Bogdan Oancea, Chimedsuren Ochir, Oluwakemi Ololade Odukoya, Felix Akpojene Ogbo, Andrew T Olagunju, Babayemi Oluwaseun Olakunde, Emad Omar, Ahmed Omar Bali, Abidemi E Emmanuel Omonisi, Sokking Ong, Obinna E Onwujekwe, Hans Orru, Doris V Ortega-Altamirano, Nikita Otstavnov, Stanislav S Otstavnov, Mayowa O Owolabi, Mahesh P A, Jagadish Rao Padubidri, Keyvan Pakshir, Adrian Pana, Demosthenes Panagiotakos, Songhomitra Panda-Jonas, Shahina Pardhan, Eun-Cheol Park, Eun-Kee Park, Fatemeh Pashazadeh Kan, Harsh K Patel, Jenil R Patel, Siddhartha Pati, Sanjay M Pattanshetty, Uttam Paudel, David M Pereira, Renato B Pereira, Arokiasamy Perianayagam, Julian David Pillay, Saeed Pirouzpanah, Farhad Pishgar, Indrashis Podder, Maarten J Postma, Hadi Pourjafar, Akila Prashant, Liliana Preotescu, Mohammad Rabiee, Navid Rabiee, Amir Radfar, Raghu Anekal Radhakrishnan, Venkatraman Radhakrishnan, Ata Rafiee, Fakher Rahim, Shadi Rahimzadeh, Mosiur Rahman, Muhammad Aziz Rahman, Amir Masoud Rahmani, Nazanin Rajai, Aashish Rajesh, Ivo Rakovac, Pradhum Ram, Kiana Ramezanzadeh, Kamal Ranabhat, Priyanga Ranasinghe, Chythra R Rao, Sowmya J Rao, Reza Rawassizadeh, Mohammad Sadegh Razeghinia, Andre M N Renzaho, Negar Rezaei, Nima Rezaei, Aziz Rezapour, Thomas J Roberts, Jefferson Antonio Buendia Rodriguez, Peter Rohloff, Michele Romoli, Luca Ronfani, Gholamreza Roshandel, Godfrey M Rwegerera, Manjula S, Siamak Sabour, Basema Saddik, Umar Saeed, Amirhossein Sahebkar, Harihar Sahoo, Sana Salehi, Marwa Rashad Salem, Hamideh Salimzadeh, Mehrnoosh Samaei, Abdallah M Samy, Juan Sanabria, Senthilkumar Sankararaman, Milena M Santric-Milicevic, Yaeesh Sardiwalla, Arash Sarveazad, Brijesh Sathian, Monika Sawhney, Mete Saylan, Ione Jayce Ceola Schneider, Mario Sekerija, Allen Seylani, Omid Shafaat, Zahra Shaghaghi, Masood Ali Shaikh, Erfan Shamsoddin, Mohammed Shannawaz, Rajesh Sharma, Aziz Sheikh, Sara Sheikhbahaei, Adithi Shetty, Jeevan K Shetty, Pavanchand H Shetty, Kenji Shibuya, Reza Shirkoohi, K M Shivakumar, Velizar Shivarov, Soraya Siabani, Sudeep K Siddappa Malleshappa, Diego Augusto Santos Silva, Jasvinder A Singh, Yitagesu Sintayehu, Valentin Yurievich Skryabin, Anna Aleksandrovna Skryabina, Matthew J Soeberg, Ahmad Sofi-Mahmudi, Houman Sotoudeh, Paschalis Steiropoulos, Kurt Straif, Ranjeeta Subedi, Mu'awiyyah Babale Sufiyan, Iyad Sultan, Saima Sultana, Daniel Sur, Viktória Szerencsés, Miklós Szócska, Rafael Tabarés-Seisdedos, Takahiro Tabuchi, Hooman Tadbiri, Amir Taherkhani, Ken Takahashi, Iman M Talaat, Ker-Kan Tan, Vivian Y Tat, Bemnet Amare A Tedla, Yonas Getaye Tefera, Arash Tehrani-Banihashemi, Mohamad-Hani Temsah, Fisaha Haile Tesfay, Gizachew Assefa Tessema, Rekha Thapar, Aravind Thavamani, Viveksandeep Thoguluva Chandrasekar, Nihal Thomas, Hamid Reza Tohidinik, Mathilde Touvier, Marcos Roberto Tovani-Palone, Eugenio Traini, Bach Xuan Tran, Khanh Bao Tran, Mai Thi Ngoc Tran, Jaya Prasad Tripathy, Biruk Shalmeno Tusa, Irfan Ullah, Saif Ullah, Krishna Kishore Umapathi, Bhaskaran Unnikrishnan, Era Upadhyay, Marco Vacante, Maryam Vaezi, Sahel Valadan Tahbaz, Diana Zuleika Velazquez, Massimiliano Veroux, Francesco S Violante, Vasily Vlassov, Bay Vo, Victor Volovici, Giang Thu Vu, Yasir Waheed, Richard G Wamai, Paul Ward, Yi Feng Wen, Ronny Westerman, Andrea Sylvia Winkler, Lalit Yadav, Seyed Hossein Yahyazadeh Jabbari, Lin Yang, Sanni Yaya, Taklo Simeneh Yazie Yazie, Yigizie Yeshaw, Naohiro Yonemoto, Mustafa Z Younis, Zabihollah Yousefi, Chuanhua Yu, Deniz Yuce, Ismaeel Yunusa, Vesna Zadnik, Fariba Zare, Mikhail Sergeevich Zastrozhin, Anasthasia Zastrozhina, Jianrong Zhang, Chenwen Zhong, Linghui Zhou, Cong Zhu, Arash Ziapour, Ivan R Zimmermann, Christina Fitzmaurice, Christopher J L Murray, Lisa M Force

Faculty, Staff and Student Publications

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden.

OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019.

EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite …

Brain Stereotactic Radiosurgery Using Mr-Guided Online Adaptive Planning For Daily Setup Variation: An End-To-End Test, Eun Young Han, He Wang, Tina Marie Briere, Debra Nana Yeboa, Themistoklis Boursianis, Georgios Kalaitzakis, Evangelos Pappas, Pamela Castillo, Jinzhong Yang

Faculty, Staff and Student Publications

Online magnetic resonance (MR)-guided radiotherapy is expected to benefit brain stereotactic radiosurgery (SRS) due to superior soft tissue contrast and capability of daily adaptive planning. The purpose of this study was to investigate daily adaptive plan quality with setup variations and to perform an end-to-end test for brain SRS with multiple metastases treated with a 1.5-Tesla MR-Linac (MRL). The RTsafe PseudoPatient Prime brain phantom was used with a delineation insert that includes two predefined structures mimicking gadolinium contrast-enhanced brain lesions. Daily adaptive plans were generated using six preset and six random setup variations. Two adaptive plans per daily MR image …

Younger Age Of Stroke In Low-Middle Income Countries Is Related To Healthcare Access And Quality, Mohammad H Rahbar, Martin Medrano, Franck Diaz-Garelli, Cosme Gonzalez Villaman, Sepideh Saroukhani, Sori Kim, Amirali Tahanan, Yahaira Franco, Gelanys Castro-Tejada, Sarah A Diaz, Manouchehr Hessabi, Sean I Savitz

Faculty, Staff and Student Publications

Stroke is the second leading cause of mortality globally with higher burden and younger age in low-middle income countries (LMICs) than high-income countries (HICs). However, it is unclear to what extent differences in healthcare access and quality (HAQ) and prevalence of risk factors between LMICs and HICs contribute to younger age of stroke in LMICs. In this systematic review, we conducted meta-analysis of 67 articles and compared the mean age of stroke between LMICs and HICs, before and after adjusting for HAQ index. We also compared the prevalence of main stroke risk factors between HICs and LMICs. The unadjusted mean …

Elucidating The Clinical Spectrum And Molecular Basis Of Hyal2 Deficiency, James Fasham, Siying Lin, Promita Ghosh, Francesca Clementina Radio, Emily G Farrow, Isabelle Thiffault, Jennifer Kussman, Dihong Zhou, Rick Hemming, Kenneth Zahka, Barry A Chioza, Lettie E Rawlins, Olivia K Wenger, Adam C Gunning, Simone Pizzi, Roberta Onesimo, Giuseppe Zampino, Emily Barker, Natasha Osawa, Megan Christine Rodriguez, Teresa M Neuhann, Elaine H Zackai, Beth Keena, Jenina Capasso, Alex V Levin, Elizabeth Bhoj, Dong Li, Hakon Hakonarson, Ingrid M Wentzensen, Adam Jackson, Kate E Chandler, Zeynep H Coban-Akdemir, Jennifer E Posey, Siddharth Banka, James R Lupski, Sarah E Sheppard, Marco Tartaglia, Barbara Triggs-Raine, Andrew H Crosby, Emma L Baple

Faculty, Staff and Student Publications

PURPOSE: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism.

METHODS: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants.

RESULTS: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and …