Biomedical Informatics Commons^™

Long-Term Morbidity And Mortality Among Survivors Of Neuroblastoma Diagnosed During Infancy: A Report From The Childhood Cancer Survivor Study, Danielle Novetsky Friedman, Pamela J Goodman, Wendy M Leisenring, Lisa R Diller, Susan L Cohn, Rebecca M Howell, Susan A Smith, Emily S Tonorezos, Suzanne L Wolden, Joseph P Neglia, Kirsten K Ness, Todd M Gibson, Paul C Nathan, Brent R Weil, Leslie L Robison, Kevin C Oeffinger, Gregory T Armstrong, Charles A Sklar, Tara O Henderson

Faculty, Staff and Student Publications

Purpose: To describe the risk of late mortality, subsequent malignant neoplasms (SMNs), and chronic health conditions (CHCs) in survivors of neuroblastoma diagnosed in infancy by treatment era and exposures.

Methods: Among 5-year survivors of neuroblastoma in the Childhood Cancer Survivor Study diagnosed age < 1 year between 1970 and 1999, we examined the cumulative incidence of late (> 5 years from diagnosis) mortality, SMN, and CHCs (grades 2-5 and 3-5). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs by decade and treatment (surgery-alone v chemotherapy with or without surgery [C ± S] v radiation with or without chemotherapy ± surgery [R ± C ± S]) among survivors and between survivors and 5,051 …

Data Mining Framework For Discovering And Clustering Phenotypes Of Atypical Diabetes, Hemang M Parikh, Cassandra L Remedios, Christiane S Hampe, Ashok Balasubramanyam, Susan P Fisher-Hoch, Ye Ji Choi, Sanjeet Patel, Joseph B Mccormick, Maria J Redondo, Jeffrey P Krischer

Faculty, Staff and Students Publications

Context: Some individuals present with forms of diabetes that are "atypical" (AD), which do not conform to typical features of either type 1 diabetes (T1D) or type 2 diabetes (T2D). These forms of AD display a range of phenotypic characteristics that likely reflect different endotypes based on unique etiologies or pathogenic processes.

Objective: To develop an analytical approach to identify and cluster phenotypes of AD.

Methods: We developed Discover Atypical Diabetes (DiscoverAD), a data mining framework, to identify and cluster phenotypes of AD. DiscoverAD was trained against characteristics of manually classified patients with AD among 278 adults with diabetes within …

Disparity In Checkpoint Inhibitor Utilization Among Commercially Insured Adult Patients With Metastatic Lung Cancer, Meng Li, Kaiping Liao, Alice J Chen, Tina Cascone, Yu Shen, Qian Lu, Ya-Chen Tina Shih

Faculty, Staff and Student Publications

BACKGROUND: There is a lack of evidence from nationwide samples on the disparity of initiating immune checkpoint inhibitors (ICIs) after metastatic lung cancer diagnosis.

METHODS: We identified metastatic lung cancer patients diagnosed between 2015 and 2020 from a large, nationwide commercial claims database. We analyzed the time from metastatic lung cancer diagnosis to ICI therapy using Cox proportional hazard models. Independent variables included county-level measures (quintiles of percentage of racialized population, quintiles of percentage of population below poverty, urbanity, and density of medical oncologists) and patient characteristics (age, sex, Charlson comorbidity index, Medicare Advantage, and year of diagnosis). All tests …

Real-Time Liver Tumor Localization Via Combined Surface Imaging And A Single X-Ray Projection, Hua-Chieh Shao, Yunxiang Li, Jing Wang, Steve Jiang, You Zhang

Faculty, Staff and Student Publications

Objective. Real-time imaging, a building block of real-time adaptive radiotherapy, provides instantaneous knowledge of anatomical motion to drive delivery adaptation to improve patient safety and treatment efficacy. The temporal constraint of real-time imaging (< 500 milliseconds) significantly limits the imaging signals that can be acquired, rendering volumetric imaging and 3D tumor localization extremely challenging. Real-time liver imaging is particularly difficult, compounded by the low soft tissue contrast within the liver. We proposed a deep learning (DL)-based framework (Surf-X-Bio), to track 3D liver tumor motion in real-time from combined optical surface image and a single on-board x-ray projection.

Approach. Surf-X-Bio performs mesh-based deformable registration to track/localize liver tumors volumetrically via three steps. First, a DL model was built to estimate liver boundary motion from an optical surface image, using learnt motion correlations between the respiratory-induced external body surface and liver boundary. Second, the residual liver boundary motion estimation error was further corrected by a graph neural network-based DL model, using information extracted from a …

Engineering T Cells To Suppress Acute Gvhd And Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation, Feiyan Mo, Norihiro Watanabe, Kayleigh I Omdahl, Phillip M Burkhardt, Xiaoyun Ding, Eiko Hayase, Angela Panoskaltsis-Mortari, Robert R Jenq, Helen E Heslop, Leslie S Kean, Malcolm K Brenner, Victor Tkachev, Maksim Mamonkin

Faculty, Staff and Student Publications

Acute graft-versus-host disease (aGVHD) limits the therapeutic benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and requires immunosuppressive prophylaxis that compromises antitumor and antipathogen immunity. OX40 is a costimulatory receptor upregulated on circulating T cells in aGVHD and plays a central role in driving the expansion of alloreactive T cells. Here, we show that OX40 is also upregulated on T cells infiltrating GVHD target organs in a rhesus macaque model, supporting the hypothesis that targeted ablation of OX40+ T cells will mitigate GVHD pathogenesis. We thus created an OX40-specific cytotoxic receptor that, when expressed on human T cells, enables selective …

Multifaceted Role For P53 In Pancreatic Cancer Suppression, Stephano S Mello, Brittany M Flowers, Pawel K Mazur, James J Lee, Fabian Müller, Sarah K Denny, Sofia Ferreira, Kathryn Hanson, Seung K Kim, William J Greenleaf, Laura D Wood, Laura D Attardi

Faculty, Staff and Student Publications

The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53's critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant-p5353,54-which we previously showed is a more robust PDAC suppressor than …

A Gene Regulatory Network Approach Harmonizes Genetic And Epigenetic Signals And Reveals Repurposable Drug Candidates For Multiple Sclerosis, Astrid M Manuel, Yulin Dai, Peilin Jia, Leorah A Freeman, Zhongming Zhao

Faculty, Staff and Student Publications

Multiple sclerosis (MS) is a complex dysimmune disorder of the central nervous system. Genome-wide association studies (GWAS) have identified 233 genetic variations associated with MS at the genome-wide significant level. Epigenetic studies have pinpointed differentially methylated CpG sites in MS patients. However, the interplay between genetic risk factors and epigenetic regulation remains elusive. Here, we employed a network model to integrate GWAS summary statistics of 14 802 MS cases and 26 703 controls with DNA methylation profiles from 140 MS cases and 139 controls and the human interactome. We identified differentially methylated genes by aggregating additive effects of differentially methylated …

Treatment Outcomes For Newly Diagnosed, Treatment-Naïve Tp53-Mutated Acute Myeloid Leukemia: A Systematic Review And Meta-Analysis, Naval G Daver, Shahed Iqbal, Camille Renard, Rebecca J Chan, Ken Hasegawa, Hao Hu, Preston Tse, Jiajun Yan, Michael J Zoratti, Feng Xie, Giridharan Ramsingh

Faculty, Staff and Student Publications

Background: TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA).

Methods: We conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), …

Microbiome Influencers Of Checkpoint Blockade-Associated Toxicity, Yinghong Wang, Robert R Jenq, Jennifer A Wargo, Stephanie S Watowich

Faculty, Staff and Student Publications

Immunotherapy has greatly improved cancer outcomes, yet variability in response and off-target tissue damage can occur with these treatments, including immune checkpoint inhibitors (ICIs). Multiple lines of evidence indicate the host microbiome influences ICI response and risk of immune-related adverse events (irAEs). As the microbiome is modifiable, these advances indicate the potential to manipulate microbiome components to increase ICI success. We discuss microbiome features associated with ICI response, with focus on bacterial taxa and potential immune mechanisms involved in irAEs, and the overall goal of driving novel approaches to manipulate the microbiome to improve ICI efficacy while avoiding irAE risk.

Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated With Diabetic Kidney Disease, Yang Pan, Xiao Sun, Xuenan Mi, Zhijie Huang, Yenchih Hsu, James E Hixson, Donna Munzy, Ginger Metcalf, Nora Franceschini, Adrienne Tin, Anna Köttgen, Michael Francis, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium Topmed Kidney Function Working Group, Jennifer A Brody, Bryan Kestenbaum, Colleen M Sitlani, Josyf C Mychaleckyj, Holly Kramer, Leslie A Lange, Xiuqing Guo, Shih-Jen Hwang, Marguerite R Irvin, Jennifer A Smith, Lisa R Yanek, Dhananjay Vaidya, Yii-Der Ida Chen, Myriam Fornage, Donald M Lloyd-Jones, Lifang Hou, Rasika A Mathias, Braxton D Mitchell, Patricia A Peyser, Sharon L R Kardia, Donna K Arnett, Adolfo Correa, Laura M Raffield, Ramachandran S Vasan, L Adrienne Cupple, Daniel Levy, Robert C Kaplan, Kari E North, Jerome I Rotter, Charles Kooperberg, Alexander P Reiner, Bruce M Psaty, Russell P Tracy, Richard A Gibbs, Alanna C Morrison, Harold Feldman, Eric Boerwinkle, Jiang He, Tanika N Kelly, Cric Study Investigators

Faculty, Staff and Students Publications

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between …

Assigning Pathogenicity For Tab2 Variants Using A Novel Scalable Functional Assay And Expanding Tab2 Disease Spectrum, Weiyi Xu, Andrea Graves, Monika Weisz-Hubshman, Lamees Hegazy, Christina Magyar, Zian Liu, Eleni Nasiotis, Md Abul Hassan Samee, Thomas Burris, Seema Lalani, Lilei Zhang

Faculty, Staff and Students Publications

Haploinsufficiency of TGF-beta-activated kinase 1 (MAP3K7) binding protein 2 (TAB2) has been associated with congenital heart disease and more recently multiorgan structural abnormalities. Missense variant represents a major proportion of non-synonymous TAB2 variants reported in gnomAD (295/576) and Clinvar (16/73), most of which are variants of uncertain significance (VUSs). However, interpretation of TAB2 missense variants remains challenging because of lack of functional assays. To address this issue, we established a cell-based luciferase assay that enables high-throughput screening of TAB2 variants to assess the functional consequence for predicting variant pathogenicity. Using this platform, we screened 47 TAB2 variants including five pathogenic …

Clinically Adjudicated Reference Standards For Evaluation Of Infectious Diseases Diagnostics, Robin Patel, Ephraim L Tsalik, Scott Evans, Vance G Fowler, Sarah B Doernberg, Antibacterial Resistance Leadership Group

Faculty, Staff and Student Publications

Lack of a gold standard can present a challenge for evaluation of diagnostic test accuracy of some infectious diseases tests, particularly when the test's accuracy potentially exceeds that of its predecessors. This approach may measure agreement with an imperfect reference, rather than correctness, because the right answer is unknown. Solutions consist of multitest comparators, including those that involve a test under evaluation if multiple new tests are being evaluated together, using latent class modeling, and clinically adjudicated reference standards. Clinically adjudicated reference standards may be considered as comparator methods when no predefined test or composite of tests is sufficiently accurate; …

Consensus Recommendations For The Use Of Automated Insulin Delivery Technologies In Clinical Practice, Moshe Phillip, Revital Nimri, Richard M Bergenstal, Katharine Barnard-Kelly, Thomas Danne, Roman Hovorka, Boris P Kovatchev, Laurel H Messer, Christopher G Parkin, Louise Ambler-Osborn, Stephanie A Amiel, Lia Bally, Roy W Beck, Sarah Biester, Torben Biester, Julia E Blanchette, Emanuele Bosi, Charlotte K Boughton, Marc D Breton, Sue A Brown, Bruce A Buckingham, Albert Cai, Anders L Carlson, Jessica R Castle, Pratik Choudhary, Kelly L Close, Claudio Cobelli, Amy B Criego, Elizabeth Davis, Carine De Beaufort, Martin I De Bock, Daniel J Desalvo, J Hans Devries, Klemen Dovc, Francis J Doyle, Laya Ekhlaspour, Naama Fisch Shvalb, Gregory P Forlenza, Geraldine Gallen, Satish K Garg, Dana C Gershenoff, Linda A Gonder-Frederick, Ahmad Haidar, Sara Hartnell, Lutz Heinemann, Simon Heller, Irl B Hirsch, Korey K Hood, Diana Isaacs, David C Klonoff, Olga Kordonouri, Aaron Kowalski, Lori Laffel, Julia Lawton, Rayhan A Lal, Lalantha Leelarathna, David M Maahs, Helen R Murphy, Kirsten Nørgaard, David O'Neal, Sean Oser, Tamara Oser, Eric Renard, Michael C Riddell, David Rodbard, Steven J Russell, Desmond A Schatz, Viral N Shah, Jennifer L Sherr, Gregg D Simonson, R Paul Wadwa, Candice Ward, Stuart A Weinzimer, Emma G Wilmot, Tadej Battelino

Faculty, Staff and Students Publications

The significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers, and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past 6 years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems …

Umbilical Cord Blood Transplantation: Connecting Its Origin To Its Future, Gabriela Sanchez-Petitto, Katayoun Rezvani, May Daher, Hind Rafei, Partow Kebriaei, Elizabeth J Shpall, Amanda Olson

Faculty, Staff and Student Publications

Transplantation of umbilical cord blood (UCB) is an attractive alternative source of hematopoietic stem cells (HSCs). The unique properties of cord blood and its distinct immune tolerance and engraftment kinetics compared to bone marrow (BM) and peripheral blood progenitor cells, permit a wider disparity in human leukocyte antigen levels between a cord blood donor and recipient after an unrelated umbilical cord blood transplant (UCBT). In addition, it is readily available and has a lowered risk of graft-versus-host disease (GvHD), with similar long-term clinical outcomes, compared to BM transplants. However, the relatively low number of cells administered by UCB units, as …

Combining Targeted Dna Repair Inhibition And Immune-Oncology Approaches For Enhanced Tumor Control, Kyle Concannon, Benjamin B Morris, Carl M Gay, Lauren A Byers

Faculty, Staff and Student Publications

Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses. Seminal studies have shown that these agents are highly effective in a pan-cancer class of tumors with genetic defects in key DNA repair genes such as BRCA1/2, BRCA-related genes, ataxia telangiectasia mutated (ATM), and others. Here, we review the molecular consequences of targeted DDR inhibition, from tumor cell death to increased …

Neoadjuvant-Adjuvant Or Adjuvant-Only Pembrolizumab In Advanced Melanoma, Sapna P Patel, Megan Othus, Yuanbin Chen, G Paul Wright, Kathleen J Yost, John R Hyngstrom, Siwen Hu-Lieskovan, Christopher D Lao, Leslie A Fecher, Thach-Giao Truong, Jennifer L Eisenstein, Sunandana Chandra, Jeffrey A Sosman, Kari L Kendra, Richard C Wu, Craig E Devoe, Gary B Deutsch, Aparna Hegde, Maya Khalil, Ankit Mangla, Amy M Reese, Merrick I Ross, Andrew S Poklepovic, Giao Q Phan, Adedayo A Onitilo, Demet G Yasar, Benjamin C Powers, Gary C Doolittle, Gino K In, Niels Kokot, Geoffrey T Gibney, Michael B Atkins, Montaser Shaheen, James A Warneke, Alexandra Ikeguchi, Jose E Najera, Bartosz Chmielowski, Joseph G Crompton, Justin D Floyd, Eddy Hsueh, Kim A Margolin, Warren A Chow, Kenneth F Grossmann, Eliana Dietrich, Victor G Prieto, Michael C Lowe, Elizabeth I Buchbinder, John M Kirkwood, Larissa Korde, James Moon, Elad Sharon, Vernon K Sondak, Antoni Ribas

Faculty, Staff and Student Publications

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.

METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year …

Adenoviral Gene Therapy For Bladder Cancer, Roland W Herzog, Masataka Suzuki

Faculty, Staff and Students Publications

Enhanced by polyamide surfactant Syn3, intravesical administration of rAd-IFNα2b results in transduction of the virus into the bladder epithelium, resulting in the synthesis and expression of local IFNα2b cytokine. Upon secretion, IFNα2b binds to the IFNα receptor on bladder cancer and other cells, resulting in signaling via the JAK-STAT pathway. A plethora of induced IFN-stimulated genes containing IFN-sensitive response elements that contribute to activation of pathways restrict cancer growth.

Epigenetic-Metabolic Interplay In The Dna Damage Response And Therapeutic Resistance Of Breast Cancer, Chandrima Das, Swagata Adhikari, Apoorva Bhattacharya, Sanjukta Chakraborty, Payel Mondal, Shalini S Yadav, Santanu Adhikary, Clayton R Hunt, Kamlesh K Yadav, Shruti Pandita, Siddhartha Roy, John A Tainer, Zamal Ahmed, Tej K Pandita

Faculty, Staff and Student Publications

Therapy resistance is imposing a daunting challenge on effective clinical management of breast cancer. Although the development of resistance to drugs is multifaceted, reprogramming of energy metabolism pathways is emerging as a central but heterogenous regulator of this therapeutic challenge. Metabolic heterogeneity in cancer cells is intricately associated with alterations of different signaling networks and activation of DNA damage response pathways. Here we consider how the dynamic metabolic milieu of cancer cells regulates their DNA damage repair ability to ultimately contribute to development of therapy resistance. Diverse epigenetic regulators are crucial in remodeling the metabolic landscape of cancer. This epigenetic-metabolic …

Bi-Allelic Tti1 Variants Cause An Autosomal-Recessive Neurodevelopmental Disorder With Microcephaly, Margaux Serey-Gaut, Marisol Cortes, Periklis Makrythanasis, Mohnish Suri, Alexander M R Taylor, Jennifer A Sullivan, Ayat N Asleh, Jaba Mitra, Mohamad A Dar, Amy Mcnamara, Vandana Shashi, Sarah Dugan, Xiaofei Song, Jill A Rosenfeld, Christelle Cabrol, Justyna Iwaszkiewicz, Vincent Zoete, Davut Pehlivan, Zeynep Coban Akdemir, Elizabeth R Roeder, Rebecca Okashah Littlejohn, Harpreet K Dibra, Philip J Byrd, Grant S Stewart, Bilgen B Geckinli, Jennifer Posey, Rachel Westman, Chelsy Jungbluth, Jacqueline Eason, Rani Sachdev, Carey-Anne Evans, Gabrielle Lemire, Grace E Vannoy, Anne O'Donnell-Luria, Frédéric Tran Mau-Them, Aurélien Juven, Juliette Piard, Cheng Yee Nixon, Ying Zhu, Taekjip Ha, Michael F Buckley, Christel Thauvin, George K Essien Umanah, Lionel Van Maldergem, James R Lupski, Tony Roscioli, Valina L Dawson, Ted M Dawson, Stylianos E Antonarakis

Faculty, Staff and Student Publications

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of …

Effects Of Protein-Coding Variants On Blood Metabolite Measurements And Clinical Biomarkers In The Uk Biobank, Abhishek Nag, Ryan S Dhindsa, Lawrence Middleton, Xiao Jiang, Dimitrios Vitsios, Eleanor Wigmore, Erik L Allman, Anna Reznichenko, Keren Carss, Katherine R Smith, Quanli Wang, Benjamin Challis, Dirk S Paul, Andrew R Harper, Slavé Petrovski

Faculty, Staff and Students Publications

Genome-wide association studies (GWASs) have established the contribution of common and low-frequency variants to metabolic blood measurements in the UK Biobank (UKB). To complement existing GWAS findings, we assessed the contribution of rare protein-coding variants in relation to 355 metabolic blood measurements-including 325 predominantly lipid-related nuclear magnetic resonance (NMR)-derived blood metabolite measurements (Nightingale Health Plc) and 30 clinical blood biomarkers-using 412,393 exome sequences from four genetically diverse ancestries in the UKB. Gene-level collapsing analyses were conducted to evaluate a diverse range of rare-variant architectures for the metabolic blood measurements. Altogether, we identified significant associations (p < 1 × 10

Identifying A Clinical Informatics Or Electronic Health Record Expert Witness For Medical Professional Liability Cases, Dean F Sittig, Adam Wright

Faculty, Staff and Student Publications

BACKGROUND: The health care field is experiencing widespread electronic health record (EHR) adoption. New medical professional liability (i.e., malpractice) cases will likely involve the review of data extracted from EHRs as well as EHR workflows, audit logs, and even the potential role of the EHR in causing harm.

OBJECTIVES: Reviewing printed versions of a patient's EHRs can be difficult due to differences in printed versus on-screen presentations, redundancies, and the way printouts are often grouped by document or information type rather than chronologically. Simply recreating an accurate timeline often requires experts with training and experience in designing, developing, using, and …

Mining For Equitable Health: Assessing The Impact Of Missing Data In Electronic Health Records, Emily Getzen, Lyle Ungar, Danielle Mowery, Xiaoqian Jiang, Qi Long

Faculty, Staff and Student Publications

Electronic health records (EHR) are collected as a routine part of healthcare delivery, and have great potential to be utilized to improve patient health outcomes. They contain multiple years of health information to be leveraged for risk prediction, disease detection, and treatment evaluation. However, they do not have a consistent, standardized format across institutions, particularly in the United States, and can present significant analytical challenges- they contain multi-scale data from heterogeneous domains and include both structured and unstructured data. Data for individual patients are collected at irregular time intervals and with varying frequencies. In addition to the analytical challenges, EHR …

A Hierarchical Strategy To Minimize Privacy Risk When Linking “De-Identified” Data In Biomedical Research Consortia, Lucila Ohno-Machado, Xiaoqian Jiang, Tsung-Ting Kuo, Shiqiang Tao, Luyao Chen, Pritham M Ram, Guo-Qiang Zhang, Hua Xu

Faculty, Staff and Student Publications

Linking data across studies offers an opportunity to enrich data sets and provide a stronger basis for data-driven models for biomedical discovery and/or prognostication. Several techniques to link records have been proposed, and some have been implemented across data repositories holding molecular and clinical data. Not all these techniques guarantee appropriate privacy protection; there are trade-offs between (a) simple strategies that can be associated with data that will be linked and shared with any party and (b) more complex strategies that preserve the privacy of individuals across parties. We propose an intermediary, practical strategy to support linkage in studies that …

A Potent And Broad Neutralization Of Sars-Cov-2 Variants Of Concern By Darpins, Vikas Chonira, Young D Kwon, Jason Gorman, James Brett Case, Zhiqiang Ku, Rudo Simeon, Ryan G Casner, Darcy R Harris, Adam S Olia, Tyler Stephens, Lawrence Shapiro, Michael F Bender, Hannah Boyd, I-Ting Teng, Yaroslav Tsybovsky, Florian Krammer, Ningyan Zhang, Michael S Diamond, Peter D Kwong, Zhiqiang An, Zhilei Chen

Faculty, Staff and Student Publications

We report the engineering and selection of two synthetic proteins-FSR16m and FSR22-for the possible treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. FSR16m and FSR22 are trimeric proteins composed of DARPin SR16m or SR22 fused with a T4 foldon. Despite selection by a spike protein from a now historical SARS-CoV-2 strain, FSR16m and FSR22 exhibit broad-spectrum neutralization of SARS-CoV-2 strains, inhibiting authentic B.1.351, B.1.617.2 and BA.1.1 viruses, with respective IC

Hla Factors Versus Non-Hla Factors For Haploidentical Donor Selection, Rohtesh S Mehta, Kai Cao, Rima M Saliba, Gheath Al-Atrash, Amin M Alousi, Konstantinos Lontos, Curtis Marcoux, Yudith Carmazzi, Gabriela Rondon, Qaiser Bashir, Chitra M Hosing, Partow Kebriaei, Issa Khouri, David Marin, Yago Nieto, Betul Oran, Uday R Popat, Muzaffar H Qazilbash, Jeremy Ramdial, Katayoun Rezvani, Richard E Champlin, Elizabeth J Shpall

Faculty, Staff and Student Publications

When multiple haploidentical donors are available for transplantation, those of younger generations are generally selected over those of older generations. However, it is unclear who is the optimal donor when selecting candidates from within a generation, such as father versus mother, son versus daughter, or brother versus sister. Although traditionally male donors are favored over female donors, particularly for male recipients, and significant associations of individual HLA mis(matches) on outcomes are being increasingly recognized, the hierarchy of factors for donor selection is indeterminate. To assess whether HLA factors take precedence over non-HLA factors and to isolate the influence of specific …

Naltrexone-Bupropion Combinations Do Not Affect Cocaine Self-Administration In Humans, Sean D Regnier, William W Stoops, Joshua A Lile, Joseph L Alcorn, B Levi Bolin, Anna R Reynolds, Lon R Hays, Abner O Rayapati, Craig R Rush

Faculty, Staff and Student Publications

The FDA has not yet approved a pharmacotherapy for cocaine use disorder despite nearly four decades of research. This study determined the initial efficacy, safety, and tolerability of naltrexone-bupropion combinations as a putative pharmacotherapy for cocaine use disorder. Thirty-one (31) non-treatment seeking participants with cocaine use disorder completed a mixed-design human laboratory study. Participants were randomly assigned to the naltrexone conditions (i.e., 0, 50 mg/day; between-subject factor) and maintained on escalating doses of bupropion (i.e., 0, 100, 200, 400 mg/day; within-subject factor) for at least four days prior to the conduct of experimental sessions. Cocaine self-administration (IN, 0, 40, 80 …

Neoadjuvant Chemotherapy Plus Nivolumab With Or Without Ipilimumab In Operable Non-Small Cell Lung Cancer: The Phase 2 Platform Neostar Trial, Tina Cascone, Cheuk H Leung, Annikka Weissferdt, Apar Pataer, Brett W Carter, Myrna C B Godoy, Hope Feldman, William N William, Yuanxin Xi, Sreyashi Basu, Jing Jing Sun, Shalini S Yadav, Frank R Rojas Alvarez, Younghee Lee, Aditya K Mishra, Lili Chen, Monika Pradhan, Haiping Guo, Ansam Sinjab, Nicolas Zhou, Marcelo V Negrao, Xiuning Le, Carl M Gay, Anne S Tsao, Lauren Averett Byers, Mehmet Altan, Bonnie S Glisson, Frank V Fossella, Yasir Y Elamin, George Blumenschein, Jianjun Zhang, Ferdinandos Skoulidis, Jia Wu, Reza J Mehran, David C Rice, Garrett L Walsh, Wayne L Hofstetter, Ravi Rajaram, Mara B Antonoff, Junya Fujimoto, Luisa M Solis, Edwin R Parra, Cara Haymaker, Ignacio I Wistuba, Stephen G Swisher, Ara A Vaporciyan, Heather Y Lin, Jing Wang, Don L Gibbons, J Jack Lee, Nadim J Ajami, Jennifer A Wargo, James P Allison, Padmanee Sharma, Humam Kadara, John V Heymach, Boris Sepesi

Faculty, Staff and Student Publications

Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7–43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6–61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. …

Immune And Pathologic Responses In Patients With Localized Prostate Cancer Who Received Daratumumab (Anti-Cd38) Or Edicotinib (Csf-1r Inhibitor), Bilal A Siddiqui, Brian F Chapin, Sonali Jindal, Fei Duan, Sreyashi Basu, Shalini S Yadav, Ai-Di Gu, Alexsandra B Espejo, Michelle Kinder, Curtis A Pettaway, John F Ward, Rebecca S S Tidwell, Patricia Troncoso, Paul G Corn, Christopher J Logothetis, Roland Knoblauch, Natalie Hutnick, Marco Gottardis, Charles G Drake, Padmanee Sharma, Sumit K Subudhi

Faculty, Staff and Student Publications

BACKGROUND: The prostate tumor microenvironment (TME) is immunosuppressive, with few effector T cells and enrichment of inhibitory immune populations, leading to limited responses to treatments such as immune checkpoint therapies (ICTs). The immune composition of the prostate TME differs across soft tissue and bone, the most common site of treatment-refractory metastasis. Understanding immunosuppressive mechanisms specific to prostate TMEs will enable rational immunotherapy strategies to generate effective antitumor immune responses. Daratumumab (anti-CD38 antibody) and edicotinib (colony-stimulating factor-1 receptor (CSF-1R) inhibitor) may alter the balance within the prostate TME to promote antitumor immune responses.

HYPOTHESIS: Daratumumab or edicotinib will be safe and …

Respiratory And Cardiometabolic Comorbidities And Stages I To Iii Nsclc Survival: A Pooled Analysis From The International Lung Cancer Consortium, Miguel García-Pardo, Amy Chang, Sabine Schmid, Mei Dong, M Catherine Brown, David Christiani, Hilary Aurora Tindel, Paul Brennan, Chu Chen, Jie Zhang, Brid M Ryan, David Zaridze, Matthew B Schabath, Leticia Ferro Leal, Rui Manuel Reis, Adonina Tardon, Guillermo Fernández-Tardon, Sanjay S Shete, Angeline Andrew, Hermann Brenner, Wei Xu, Rayjean J Hung, Geoffrey Liu

Faculty, Staff and Student Publications

INTRODUCTION: We explored the association of respiratory and cardiometabolic comorbidities with NSCLC overall survival (OS) and lung cancer-specific survival (LCSS), by stage, in a large, multicontinent NSCLC pooled data set.

METHODS: On the basis of patients pooled from 11 International Lung Cancer Consortium studies with available respiratory and cardiometabolic comorbidity data, adjusted hazard ratios (aHRs) were estimated using Cox models for OS. LCSS was evaluated using competing risk Grey and Fine models and cumulative incidence functions. Logistic regression (adjusted OR [aOR]) was applied to assess factors associated with surgical resection.

RESULTS: OS analyses used patients with NSCLC with respiratory health …

Factors That Influence Treatment Decisions: A Qualitative Study Of Racially And Ethnically Diverse Patients With Low- And Very-Low Risk Prostate Cancer, Alice Guan, Janet K Shim, Laura Allen, Mei-Chin Kuo, Kathie Lau, Zinnia Loya, James D Brooks, Peter R Carroll, Iona Cheng, Benjamin I Chung, Mindy C Derouen, Dominic L Frosch, Todd Golden, John T Leppert, Daphne Y Lichtensztajn, Qian Lu, Debora L Oh, Weiva Sieh, Michelle Wadhwa, Scarlett L Gomez, Salma Shariff-Marco

Faculty, Staff and Student Publications

BACKGROUND: Factors that influence prostate cancer treatment decisions are complex, multifaceted, and personal, and may vary by race/ethnicity. Although research has been published to quantify factors involved in decision-making, these studies have been limited to primarily white, and to a lesser extent, Black patients, and quantitative studies are limited for discerning the cultural and contextual processes that shape decision-making.

METHODS: We conducted 43 semi-structured interviews with a racially and ethnically diverse sample of patients diagnosed with low- and very-low risk prostate cancer who had undergone treatment for their prostate cancer. Interviews were transcribed, independently coded, and analyzed to identify themes …