Digital Commons Network^™

The Associations Of Sensory Impairment With 10-Year Risk Of Dementia And Alzheimer's Disease: The Health And Retirement Study, 2010-2020, Kun Li, Rahul Ghosal, Donglan Zhang, Yike Li, Matthew C Lohman, Monique J Brown, Anwar T Merchant, Chih-Hsiang Yang, Jean Neils-Strunjas, Daniela B Friedman, Jingkai Wei

Faculty, Staff and Student Publications

Background: Studies have examined the association between dual sensory impairment and late-life cognitive outcomes in the U.S with inconsistent findings.

Objective: To examine the associations between sensory impairment and 10-year risk of dementia or Alzheimer's disease among U.S. adults aged ≥ 50.

Methods: A prospective cohort study based on the Health and Retirement Study from 2010 to 2020. Individuals aged ≥ 50 years without self-reported dementia and Alzheimer's disease in 2010 were included in the analysis. Self-reported visual and hearing impairments were measures in 2010. Main failure events included self-reported incident dementia and Alzheimer's disease over a 10-year follow-up period. …

Depletion Of Acetyl-Coa Carboxylase 1 Facilitates Epithelial-Mesenchymal Transition In Prostate Cancer Cells By Activating The Mapk/Erk Pathway, Jiarun Lai, Shaoyou Liu, Yupeng Chen, Jian Chen, Jinchuang Li, Zhenguo Liang, Xinyue Mei, Yuanfa Feng, Zhaodong Han, Funeng Jiang, Shengbang Yang, Yongding Wu, Huijing Tan, Junchen Liu, Huichan He, Weide Zhong

Faculty, Staff and Student Publications

Hyperactivation of fatty acid biosynthesis holds promise as a targeted therapeutic strategy in prostate cancer (PCa). However, inhibiting these enzymes could potentially promote metastatic progression in various other cancers. Herein, we found that depletion of acetyl-CoA carboxylase 1 (encoded by ACACA), the enzyme responsible for the first and rate-limiting step of de novo fatty acid biosynthesis, facilitated epithelial-mesenchymal transition (EMT) and migration of PCa cells. This finding was validated in vitro through cell migration assays and in vivo using a metastatic model established by tail vein injection of ACACA-depleted cells into BALB/c nude mice. Additionally, depletion of ACACA activated the …

Oxidized Carbon Nanoparticles Enhance Cellular Energetics With Application To Injured Brain, Karthik Mouli, Anton V Liopo, Emily A Mchugh, Erica Underwood, Jing Zhao, Pramod K Dash, Anh T T Vo, Vikas H Malojirao, Muralidhar L Hegde, James M Tour, Paul J Derry, Thomas A Kent

Faculty, Staff and Student Publications

Pro-energetic effects of functionalized, oxidized carbon nanozymes (OCNs) are reported. OCNs, derived from harsh acid oxidation of single-wall carbon nanotubes or activated charcoal are previously shown to possess multiple nanozymatic activities including mimicking superoxide dismutase and catalyzing the oxidation of reduced nicotinamide adenine dinucleotide (NADH) to NAD+. These actions are predicted to generate a glycolytic shift and enhance mitochondrial energetics under impaired conditions. Impaired mitochondrial energy metabolism is increasingly recognized as an important facet of traumatic brain injury (TBI) pathophysiology and decreases the efficiency of electron transport chain (ETC)-coupled adenosine triphosphate (ATP) and NAD+ regeneration. In vitro, OCNs promote a …

Endovascular Therapy In Patients With Acute Ischemic Stroke With Large Infarct: A Guideline From The Society Of Vascular And Interventional Neurology, Maxim Mokin, Tudor G Jovin, Sunil A Sheth, Thanh N Nguyen, Kaiz S Asif, Ameer E Hassan, Ashutosh P Jadhav, Cynthia Kenmuir, David S Liebeskind, Ossama Mansour, Raul G Nogueira, Robin Novakovic, Santiago Ortega-Gutierrez, Albert J Yoo, Waldo R Guerrero, Amer M Malik

Faculty, Staff and Student Publications

Background: Recent randomized clinical trials of endovascular therapy in patients with large infarct provided new evidence in support of endovascular interventions in patients with acute ischemic stroke. The Society of Vascular and Interventional Neurology Guidelines and Practice Standards committee aims to provide up-to-date recommendations on focused relevant clinical questions. Here, we review current evidence and provide recommendations for the selection and endovascular treatment of patients with anterior circulation large vessel occlusion and large infarct.

Methods: The Society of Vascular and Interventional Neurology Guidelines and Practice Standards committee assembled a writing group and recruited interdisciplinary experts to review and evaluate the …

Nulliparous With Class Iii Obesity At Term: Labor Induction Or Cesarean Delivery Without Labor, Yossi Bart, Rachel L Wiley, Ipsita Ghose, Michal Fishel Bartal, Khalil M Chahine, Suneet P Chauhan, Sean Blackwell, Baha M Sibai

Faculty, Staff and Student Publications

Objective: This study aimed to compare maternal and neonatal outcomes between labor induction versus cesarean delivery (CD) without labor among nulliparous individuals with class III obesity (body mass index [BMI] ≥40 kg/m2).

Study design: A retrospective cohort study of all nulliparous singleton deliveries at ≥37 weeks with a BMI of ≥40 kg/m2 at delivery between March 2020 and February 2022. We excluded individuals with spontaneous labor, fetal malformations, and stillbirths. The primary outcome was a composite of maternal mortality and morbidity, including infectious and hemorrhagic morbidity. The secondary outcome was a neonatal composite. A subgroup analysis evaluated patients with a …

Intra- And Postoperative Complications In 4565 Vnotes Hysterectomies: International Registry Cohort Study., Andrea Stuart, Johanna Wagenius, Levon Badiglian-Filho, Jens Schnabel, Alvaro Montealegre, Sophia Ehrström, Michael Hartmann, Jona Vercammen, Daniela Huber, Anna Lingström, Jan Baekelandt

Faculty, Staff and Student Publications

Objective: To present the rates of intra- and postoperative complications and conversions in a large cohort of unselected vNOTES hysterectomies, performed by surgeons with different levels of expertise.

Design: International register-based cohort study.

Setting: Hysterectomies in the iNOTESs registry, 2015 to January 2024, performed by 201 surgeons from multiple countries.

Population: 4565 patients undergoing vNOTES hysterectomy.

Methods: Descriptive data are presented in frequencies (n) and percent (%).

Main outcome measure: Intra- and postoperative complications. Conversions.

Results: Intraoperative and postoperative complication rates were 3.2% (n = 144) and 2.5% (n = 115), respectively. Conversions occurred in 1.6% (n = 72), of …

Curq+ With Resveratrol Diminish Joint Pain In A Child With Pseudoachondroplasia: A Case Report, Jacqueline T Hecht, Ana-Coral Barreda-Bonis, Karen L Posey

Faculty, Staff and Student Publications

This case report details the successful use of over-the-counter resveratrol and CurQ+ in a five-year-old with pseudoachondroplasia (PSACH), a severe dwarfing condition caused by mutations in cartilage oligomeric matrix protein (COMP). Disproportionate short stature, abnormal joints, joint deformities, and pain starting in early childhood are characteristic findings. Adult treatments include non-steroidal anti-inflammatory drugs (NSAIDs) and joint replacement to manage joint pain. Childhood pain goes largely untreated given the concern of daily use of NSAIDs in the very young. Recently, resveratrol has been shown to reduce pain and CurQ+ improves growth in a mouse model of PSACH. The use of these …

Liver Involvement In A Large Cohort Of Patients With Erythropoietic Protoporphyria Or X-Linked Protoporphyria, Cynthia Levy, Hetanshi Naik, Jessica Overbey, Karli Hedstrom, Kelly Wang, Catherine Mcdonough, Mary Freeman, Siobán B Keel, Angelika L Erwin, Amy K Dickey, Rebecca K Leaf, John Quigley, Marshall Mazepa, Bruce Wang, John Phillips, Charles Parker, Brendan Mcguire, Mohamed Kazamel, Herbert Bonkovsky, Sean Rudnick, Karl E Anderson, Akshata Moghe, Manish Thapar, Behnam Saberi, Kristen Wheeden, Robert Desnick, Manisha Balwani, Porphyrias Consortium Of The Rare Diseases Clinical Research Network

Faculty, Staff and Student Publications

Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by the accumulation of protoporphyrin in the marrow, erythrocytes, plasma, skin, and liver, and present clinically with painful cutaneous phototoxicity. Liver abnormalities have been reported in over 25% of patients with EPP. Further characterization of liver involvement in protoporphyria is needed.

Methods: Patients with EPP or XLP enrolled in the longitudinal studies of the NIH-supported Porphyrias Consortium were included. Medical history, laboratory, and liver histology data were abstracted and described.

Results: A total of 322 patients were enrolled; 28 (8.7%) had XLP, 52% were female, and the median age at …

Assessment Of Skin Fibrosis In A Murine Model Of Systemic Sclerosis With Multifunctional Optical Coherence Tomography, Harshdeep Singh Chawla, Yanping Chen, Minghua Wu, Pavel Nikitin, Jessica Gutierrez, Chandra Mohan, Manmohan Singh, Salavat R Aglyamov, Shervin Assassi, Kirill V Larin

Faculty, Staff and Student Publications

Significance: Systemic sclerosis (SSc) is a chronic idiopathic disease that causes immune dysregulation, vasculopathy, and organ fibrosis that affects more than 3 million people in the US alone. The modified Rodnan skin score (mRSS) is the current gold standard for diagnosing and staging skin fibrosis in SSc. However, mRSS is subjective, requires extensive training, and has high observer variability.

Aim: We aim to provide a quantitative method for the assessment of fibrosis.

Approach: We utilized optical coherence tomography (OCT), its extensions, optical coherence elastography (OCE), and OCT angiography (OCTA) to evaluate SSc-like fibrosis and therapy response in a mouse model. …

Relapsed Acute Myeloid Leukemia With Early Presentation As Leukemia Cutis, Refractory To Second-Line Treatment, Emin Gayibov, Aditi Karambelkar, Virushnee Senthilkumar, Amita J Dsouza, Amit K Correa

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a hematologic malignancy with a poor prognosis, often presenting with systemic and extramedullary manifestations. Leukemia cutis (LC), the infiltration of leukemic cells into the skin, is a rare and clinically significant complication of AML. It often signals extramedullary disease involvement, may precede systemic relapse, and is associated with poor survival outcomes. We report the case of a 36-year-old female with AML who developed recurrent, reddish-brown nodular skin lesions on the face, trunk, and extremities, consistent with LC. Despite achieving initial remission with induction and consolidation chemotherapy, she experienced early LC recurrence, pancytopenia, hepatobiliary dysfunction, and …

Safety And Efficacy Of Dtx401, An Aav8-Mediated Liver-Directed Gene Therapy, In Adults With Glycogen Storage Disease Type I A (Gsdia), David A Weinstein, Terry G Derks, David F Rodriguez-Buritica, Ayesha Ahmad, María-Luz Couce, John J Mitchell, Rebecca Riba-Wolman, Malaya Mount, Julieta Bonvin Sallago, Katalin M Ross, Melanie M Van Der Klauw, Foekje De Boer, Caroline Van Der Schaaf, Heather Saavedra, Miguel Martínez-Olmos, Elvis Atanga, Asad Hosseini, Deepali Mitragotri, Eric Crombez

Faculty, Staff and Student Publications

Glycogen storage disease type Ia (GSDIa) is a rare, life‐threatening, inherited carbohydrate metabolism disorder caused by glucose‐6‐phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno‐associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. This open‐label, phase 1/2, dose‐escalation, 52‐week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × …

Factors Affecting Waiting Times To Enter Opioid Use Disorder Treatment In The United States With A Particular Focus On Potential Biological Sex Disparity, Stanley Nkemjika, Kenneth Oforeh, Connie Olwit, Olaniyi Olayinka, Terence Tumenta

Faculty, Staff and Student Publications

Aim: Opioid use disorder (OUD) is the problematic use of licit or illicit opioids. Thus far, the literature on biological sex differences in accessing treatment is scarce. Hence, we hypothesize that biological sex has a moderating effect on OUD treatment accessibility. We aim to explore biological sex differences in treatment disparities and its role in wait time to enter OUD treatment.

Method: Using the 2018 Treatment Episode Data Set Discharge, the national sample representative of OUD patients in the substance use disorder treatment facilities within the 50 states of the United States was 382,547. Univariate and multivariable logistic analysis of …

[Treatment Adherence For Attention Deficit Hyperactivity Disorder (Adhd) In The Champ Ut-Health Houston Program], Rachitha P Jadala, Hali Temkin, Kerri L Daniel, Cesar A Soutullo

Faculty, Staff and Student Publications

Introduction: ADHD has a safe and effective treatment, but treatment adherence is often low. Several factors contribute to this low adherence, some of which are modifiable.

Methods: We conducted a literature review of recent studies on medication adherence in children and adolescents with ADHD. We gathered data on ADHD treatment adherence from our clinic in the ADHD Program and the Child and Adolescent Mood Disorders Program (ChAMP) at the University of Texas Health-Houston Program. We analyzed factors related to medication adherence, such as patient age, sex, prescription type, release formula, and their association with adherence in 117 patients with ADHD …

A Multilevel Latent Class Analysis Of Adolescent Engagement In Interpersonal Violence: The Role Of Stressful Life Events, School Climate, And School Characteristics, Yu Lu, Sabina Low, Shristi Bhochhibhoya, Adriana Dragicevic, Elizabeth Baumler, Jeff R Temple

Faculty, Staff and Student Publications

Objective: Little is known about the role of school-level factors in adolescent violence. Using multilevel latent class analysis, we identified groups of adolescents and schools based on adolescent involvement in violent behaviors and assessed how these group memberships differed by individual and school characteristics.

Method: We used baseline data from a randomized controlled trial of a school-based violence prevention program. Participants included 2,768 adolescents (Meanage=13 years) enrolled in 7th grade across 24 public schools in southeast Texas.

Results: We identified three classes of adolescents, including a Non-violent class (74.5%), a Moderately Violent class (20.0%), and a Highly Violent class (5.4%). …

Maximizing Benefits For Our Local Authors, Joanne Romano

Library Staff Publications

Our library's publishing benefits include TA's, instructional LibGuides, predatory publisher data and other resources to share with six academic stakeholders. Keeping our authors informed of these benefits requires creative thinking. In this presentation, our resource management team shares ideas for maximizing benefits for local authors at reasonable and sustainable costs.

Targeting The Mycn-Mdm2 Pathways For Cancer Therapy: Are They Druggable?, Wei Wang, Yi Du, Sayantap Datta, Josef F Fowler, Hannah T Sang, Najah Albadari, Wei Li, Jennifer Foster, Ruiwen Zhang

Faculty, Staff and Students Publications

Targeting oncogenes and their interactive partners is an effective approach to developing novel targeted therapies for cancer and other chronic diseases. We and others have long suggested the MDM2 oncogene being an excellent target for cancer therapy, based on its p53-dependent and -independent oncogenic activities in a variety of cancers. The MYC family proteins are transcription factors that also regulate diverse biological functions. Dysregulation of MYC, such as amplification of MYCN, is associated with tumorigenesis, especially for neuroblastoma. Although the general survival rate of neuroblastoma patients has significantly improved over the past few decades, high-risk neuroblastoma still presents a …

Space Flight Missions Over 6 Months Significantly Increase The Risk Of Shoulder Pathology And Rotator Cuff Tears, Benjamin Fiedler, Meghana Jami, Srikhar V Chilukuri, Abdullah Ghali, Todd Phillips, Adil Shahzad Ahmed

Faculty, Staff and Students Publications

Background: The purpose of this study was to determine risk of shoulder injury in astronauts returning from space flight and highlight the need for further exploration of risk factors and preventative strategies.

Methods: Using The Lifetime Surveillance of Astronaut Health epidemiology database at National Aeronautics and Space Administration, a retrospective cohort study was conducted to assess the effect of space flight mission duration on rate of shoulder injury among astronauts. Inclusion criteria were all astronauts who participated in space flight regardless of age or space flight mission time. Exclusion criteria were all injuries occurring greater than 5 years following return …

Advances In Idiopathic Pulmonary Fibrosis Diagnosis And Treatment, Hongli Liu, Jiaxi Shen, Chao He

Faculty, Staff and Students Publications

Significant advances have been made in diagnosing and treating idiopathic pulmonary fibrosis (IPF) in the last decade. The incidence and prevalence of IPF are increasing, and morbidity and mortality remain high despite the two Food and Drug Administration (FDA)-approved medications, pirfenidone and nintedanib. Hence, there is an urgent need to develop new diagnostic tools and effective therapeutics to improve early, accurate diagnosis of IPF and halt or reverse the progression of fibrosis with a better safety profile. New diagnostic tools such as transbronchial cryobiopsy and genomic classifier require less tissue and generally have good safety profiles, and they have been …

Canonical And Non-Canonical Functions Of The Non-Coding Rna Component (Terc) Of Telomerase Complex, Chongwen Cao, Weiyi Gong, Yuanlong Shuai, Sara Rasouli, Qianyun Ge, Anam Khan, Aleksandra Dakic, Nagireddy Putluri, Gennady Shvets, Yun-Ling Zheng, Danyal Daneshdoust, Rani Mahyoob, Jenny Li, Xuefeng Liu

Faculty, Staff and Students Publications

The telomerase complex consists of a protein component (TERT), which has reverse transcriptase activity, and an RNA component (TERC), which serves as a template for telomere synthesis. Evidence is rapidly accumulating regarding the non-canonical functions of these components in both normal or diseased cells. An oligonucleotide-based drug, the first telomerase inhibitor, secured FDA approval in June 2024. We recently summarized the non-canonical functions of TERT in viral infections and cancer. In this review, we expand on these non-canonical functions of TERC beyond telomere maintenance. Specifically, we explore TERC's roles in cellular aging and senescence, immune regulation, genetic diseases, human cancer, …

Multiscale 3d Spatial Analysis Of The Tumor Microenvironment Using Whole-Tissue Digital Histopathology, Daniel Shafiee Kermany, Ju Young Ahn, Matthew Vasquez, Weijie Zhang, Lin Wang, Kai Liu, Zhan Xu, Min Soon Cho, Wendolyn Carlos-Alcalde, Hani Lee, Raksha Raghunathan, Jianting Sheng, Xiaoxin Hao, Hong Zhao, Vahid Afshar-Kharghan, Xiang Hong-Fei Zhang, Stephen Tin Chi Wong

Faculty, Staff and Students Publications

No abstract provided.

Genomics And Multiomics In The Age Of Precision Medicine, Srinivasan Mani, Seema R Lalani, Mohan Pammi

Faculty, Staff and Students Publications

Precision medicine is a transformative healthcare model that utilizes an understanding of a person's genome, environment, lifestyle, and interplay to deliver customized healthcare. Precision medicine has the potential to improve the health and productivity of the population, enhance patient trust and satisfaction in healthcare, and accrue health cost-benefits both at an individual and population level. Through faster and cost-effective genomics data, next-generation sequencing has provided us the impetus to understand the nuances of complex interactions between genes, diet, and lifestyle that are heterogeneous across the population. The emergence of multiomics technologies, including transcriptomics, proteomics, epigenomics, metabolomics, and microbiomics, has enhanced …

Evaluation Of Enzyme Activity Predictions For Variants Of Unknown Significance In Arylsulfatase A, Shantanu Jain, Marena Trinidad, Thanh Binh Nguyen, Kaiya Jones, Santiago Diaz Neto, Fang Ge, Ailin Glagovsky, Cameron Jones, Giankaleb Moran, Boqi Wang, Kobra Rahimi, Sümeyra Zeynep Çalıcı, Luis R Cedillo, Silvia Berardelli, Buse Özden, Ken Chen, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Sadhna Rana, Swatantra Pradhan, Rajgopal Srinivasan, Rakshanda Sajeed, Dinesh Joshi, Eshel Faraggi, Robert Jernigan, Andrzej Kloczkowski, Jierui Xu, Zigang Song, Selen Özkan, Natàlia Padilla, Xavier De La Cruz, Rocio Acuna-Hidalgo, Andrea Grafmüller, Laura T Jiménez Barrón, Matteo Manfredi, Castrense Savojardo, Giulia Babbi, Pier Luigi Martelli, Rita Casadio, Yuanfei Sun, Shaowen Zhu, Yang Shen, Fabrizio Pucci, Marianne Rooman, Gabriel Cia, Daniele Raimondi, Pauline Hermans, Sofia Kwee, Ella Chen, Courtney Astore, Akash Kamandula, Vikas Pejaver, Rashika Ramola, Michelle Velyunskiy, Daniel Zeiberg, Reet Mishra, Teague Sterling, Jennifer L Goldstein, Jose Lugo-Martinez, Sufyan Kazi, Sindy Li, Kinsey Long, Steven E Brenner, Constantina Bakolitsa, Predrag Radivojac, Dean Suhr, Teryn Suhr, Wyatt T Clark

Faculty, Staff and Students Publications

Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfatase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning …

Cagi6 Id Panel Challenge: Assessment Of Phenotype And Variant Predictions In 415 Children With Neurodevelopmental Disorders (Ndds), Maria Cristina Aspromonte, Alessio Del Conte, Shaowen Zhu, Wuwei Tan, Yang Shen, Yexian Zhang, Qi Li, Maggie Haitian Wang, Giulia Babbi, Samuele Bovo, Pier Luigi Martelli, Rita Casadio, Azza Althagafi, Sumyyah Toonsi, Maxat Kulmanov, Robert Hoehndorf, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Su Xian, Wesley Surento, Vikas Pejaver, Sean D Mooney, Uma Sunderam, Rajgopal Srinivasan, Alessandra Murgia, Damiano Piovesan, Silvio C E Tosatto, Emanuela Leonardi

Faculty, Staff and Students Publications

The Genetics of Neurodevelopmental Disorders Lab in Padua provided a new intellectual disability (ID) Panel challenge for computational methods to predict patient phenotypes and their causal variants in the context of the Critical Assessment of the Genome Interpretation, 6th edition (CAGI6). Eight research teams submitted a total of 30 models to predict phenotypes based on the sequences of 74 genes (VCF format) in 415 pediatric patients affected by Neurodevelopmental Disorders (NDDs). NDDs are clinically and genetically heterogeneous conditions, with onset in infant age. Here, we assess the ability and accuracy of computational methods to predict comorbid phenotypes based on clinical …

Assessing Predictions On Fitness Effects Of Missense Variants In Hmbs In Cagi6, Jing Zhang, Lisa Kinch, Panagiotis Katsonis, Olivier Lichtarge, Milind Jagota, Yun S Song, Yuanfei Sun, Yang Shen, Nurdan Kuru, Onur Dereli, Ogun Adebali, Muttaqi Ahmad Alladin, Debnath Pal, Emidio Capriotti, Maria Paola Turina, Castrense Savojardo, Pier Luigi Martelli, Giulia Babbi, Rita Casadio, Fabrizio Pucci, Marianne Rooman, Gabriel Cia, Matsvei Tsishyn, Alexey Strokach, Zhiqiang Hu, Warren Van Loggerenberg, Frederick P Roth, Predrag Radivojac, Steven E Brenner, Qian Cong, Nick V Grishin

Faculty, Staff and Students Publications

This paper presents an evaluation of predictions submitted for the "HMBS" challenge, a component of the sixth round of the Critical Assessment of Genome Interpretation held in 2021. The challenge required participants to predict the effects of missense variants of the human HMBS gene on yeast growth. The HMBS enzyme, critical for the biosynthesis of heme in eukaryotic cells, is highly conserved among eukaryotes. Despite the application of a variety of algorithms and methods, the performance of predictors was relatively similar, with Kendall's tau correlation coefficients between predictions and experimental scores around 0.3 for a majority of submissions. Notably, the …

Evaluating Predictors Of Kinase Activity Of Stk11 Variants Identified In Primary Human Non-Small Cell Lung Cancers, Yile Chen, Kyoungyeul Lee, Junwoo Woo, Dong-Wook Kim, Changwon Keum, Giulia Babbi, Rita Casadio, Pier Luigi Martelli, Castrense Savojardo, Matteo Manfredi, Yang Shen, Yuanfei Sun, Panagiotis Katsonis, Olivier Lichtarge, Vikas Pejaver, David J Seward, Akash Kamandula, Constantina Bakolitsa, Steven E Brenner, Predrag Radivojac, Anne O'Donnell-Luria, Sean D Mooney, Shantanu Jain

Faculty, Staff and Students Publications

Critical evaluation of computational tools for predicting variant effects is important considering their increased use in disease diagnosis and driving molecular discoveries. In the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, a dataset of 28 STK11 rare variants (27 missense, 1 single amino acid deletion), identified in primary non-small cell lung cancer biopsies, was experimentally assayed to characterize computational methods from four participating teams and five publicly available tools. Predictors demonstrated a high level of performance on key evaluation metrics, measuring correlation with the assay outputs and separating loss-of-function (LoF) variants from wildtype-like (WT-like) variants. The …

Predicting The Impact Of Rare Variants On Rna Splicing In Cagi6, Jenny Lord, Carolina Jaramillo Oquendo, Htoo A Wai, Andrew G L Douglas, David J Bunyan, Yaqiong Wang, Zhiqiang Hu, Zishuo Zeng, Daniel Danis, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Yuchen Chang, Richard D Bagnall, Stephen M Mount, Brynja Matthiasardottir, Chiaofeng Lin, Thomas Van Overeem Hansen, Raphael Leman, Alexandra Martins, Claude Houdayer, Sophie Krieger, Constantina Bakolitsa, Yisu Peng, Akash Kamandula, Predrag Radivojac, Diana Baralle

Faculty, Staff and Students Publications

Variants which disrupt splicing are a frequent cause of rare disease that have been under-ascertained clinically. Accurate and efficient methods to predict a variant's impact on splicing are needed to interpret the growing number of variants of unknown significance (VUS) identified by exome and genome sequencing. Here, we present the results of the CAGI6 Splicing VUS challenge, which invited predictions of the splicing impact of 56 variants ascertained clinically and functionally validated to determine splicing impact. The performance of 12 prediction methods, along with SpliceAI and CADD, was compared on the 56 functionally validated variants. The maximum accuracy achieved was …

Genomic Balancing Act: Deciphering Dna Rearrangements In The Complex Chromosomal Aberration Involving 5p152, 2q311, And 18q2132, Zain Dardas, Dana Marafi, Ruizhi Duan, Jawid M Fatih, Omnia F El-Rashidy, Christopher M Grochowski, Claudia M B Carvalho, Shalini N Jhangiani, Weimin Bi, Haowei Du, Richard A Gibbs, Jennifer E Posey, Daniel G Calame, Maha S Zaki, James R Lupski

Faculty, Staff and Students Publications

Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and a terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses …

Analysis And Benchmarking Of Small And Large Genomic Variants Across Tandem Repeats, Adam C English, Egor Dolzhenko, Helyaneh Ziaei Jam, Sean K Mckenzie, Nathan D Olson, Wouter De Coster, Jonghun Park, Bida Gu, Justin Wagner, Michael A Eberle, Melissa Gymrek, Mark J P Chaisson, Justin M Zook, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Tandem repeats (TRs) are highly polymorphic in the human genome, have thousands of associated molecular traits and are linked to over 60 disease phenotypes. However, they are often excluded from at-scale studies because of challenges with variant calling and representation, as well as a lack of a genome-wide standard. Here, to promote the development of TR methods, we created a catalog of TR regions and explored TR properties across 86 haplotype-resolved long-read human assemblies. We curated variants from the Genome in a Bottle (GIAB) HG002 individual to create a TR dataset to benchmark existing and future TR analysis methods. We …

Meeting Report: 1st International Conference On Polyploid Giant Cancer Cells-Biology, Clinical Applications, And The Birth Of A New Field In Cancer Research, Tao P Wu, Xiaoran Li, Sujuan Ba, Phil Jones, Donna E Hansel, Jinsong Liu

Faculty, Staff and Students Publications

No abstract provided.

Use Of Robust Norming To Create A Sensitive Cognitive Summary Score In De Novo Parkinson's Disease: An Illustrative Example, Daniel Weintraub, Michael C Brumm, Ryan Kurth, Michele K York

Faculty, Staff and Students Publications

Background: Cognitive impairment is common at all stages of Parkinson's disease (PD), but there is no consensus on which neuropsychological tests to use or how to interpret cognitive battery results. A cognitive summary score (CSS) combines the richness of a neuropsychological battery with the simplicity of a single score.

Objective: The objective of this study was to determine whether a CSS created using robust norming can detect early cognitive deficits in de novo, untreated PD.

Methods: Baseline cognitive data from PD participants and healthy control participants (HCs) in the Parkinson's Progression Markers Initiative were used to (1) create a robust …