Life Sciences Commons^™

Technical And Regulatory Considerations For Taking Liquid Biopsy To The Clinic: Validation Of The Jax Plasmamonitor, Bridgette Sisson, Jasmina Uvalic, Kevin Kelly, Pavalan Selvam, Andrew N Hesse, Guruprasad Ananda, Harshpreet Chandok, Daniel Bergeron, Lauren Holinka, Honey V Reddi

Faculty Research 2019

The standard of care in oncology has been genomic profiling of tumor tissue biopsies for the treatment and management of disease, which can prove to be quite challenging in terms of cost, invasiveness of procedure, and potential risk for the patient. As the number of available drugs in oncology continues to increase, so too does the demand for technologies and testing applications that can identify genomic alterations targetable by these new therapies. Liquid biopsies that use a blood draw from the diseased patient may offset the many disadvantages of the invasive procedure. However, as with any new technology or finding …

The Global State Of The Genetic Counseling Profession., Maryann Abacan, Lamia Alsubaie, Kristine Barlow-Stewart, Beppy Caanen, Christophe Cordier, Eliza Courtney, Emeline Davoine, Janice Edwards, Niby J Elackatt, Kate Gardiner, Yue Guan, Lian-Hua Huang, Charlotta Ingvoldstad Malmgren, Sahil Kejriwal, Hyon J Kim, Deborah Lambert, Paulina Araceli Lantigua-Cruz, Juliana M H Lee, Marianne Lodahl, Åshild Lunde, Shelley Macaulay, Ivan Macciocca, Sonia Margarit, Anna Middleton, Ramona Moldovan, Joanne Ngeow, Alexandra J Obregon-Tito, Kelly E Ormond, Milena Paneque, Karen Powell, Kunal Sanghavi, Diana Scotcher, Jenna Scott, Clara Serra Juhé, Shiri Shkedi-Rafid, Tina-Marié Wessels, Sook-Yee Yoon, Catherine Wicklund

Faculty Research 2019

The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic …

Metformin Intervention Prevents Cardiac Dysfunction In A Murine Model Of Adult Congenital Heart Disease., Julia C Wilmanns, Raghav Pandey, Olivia Hon, Anjana Chandran, Jan M Schilling, Elvira Forte, Qizhu Wu, Gael Cagnone, Preeti Bais, Vivek M. Philip, David Coleman, Heidi Kocalis, Stuart K Archer, James T Pearson, Mirana Ramialison, Joerg Heineke, Hemal H Patel, Nadia Rosenthal, Milena B Furtado, Mauro W Costa

Faculty Research 2019

OBJECTIVE: Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown.

METHODS: We used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention …

Bifet: Sequencing Bias-Free Transcription Factor Footprint Enrichment Test., Ahrim Youn, Eladio J Marquez, Nathan Lawlor, Michael L. Stitzel, Duygu Ucar

Faculty Research 2019

Transcription factor (TF) footprinting uncovers putative protein-DNA binding via combined analyses of chromatin accessibility patterns and their underlying TF sequence motifs. TF footprints are frequently used to identify TFs that regulate activities of cell/condition-specific genomic regions (target loci) in comparison to control regions (background loci) using standard enrichment tests. However, there is a strong association between the chromatin accessibility level and the GC content of a locus and the number and types of TF footprints that can be detected at this site. Traditional enrichment tests (e.g. hypergeometric) do not account for this bias and inflate false positive associations. Therefore, we …

Gopher: Generator Of Probes For Capture Hi-C Experiments At High Resolution., Peter Hansen, Salaheddine Ali, Hannah Blau, Daniel Danis, Jochen Hecht, Uwe Kornak, Darío G Lupiáñez, Stefan Mundlos, Robin Steinhaus, Peter N Robinson

Faculty Research 2019

BACKGROUND: Target enrichment combined with chromosome conformation capturing methodologies such as capture Hi-C (CHC) can be used to investigate spatial layouts of genomic regions with high resolution and at scalable costs. A common application of CHC is the investigation of regulatory elements that are in contact with promoters, but CHC can be used for a range of other applications. Therefore, probe design for CHC needs to be adapted to experimental needs, but no flexible tool is currently available for this purpose.

RESULTS: We present a Java desktop application called GOPHER (Generator Of Probes for capture Hi-C Experiments at high Resolution) …

An Ontological Foundation For Ocular Phenotypes And Rare Eye Diseases., Panagiotis I Sergouniotis, Emmanuel Maxime, Dorothée Leroux, Annie Olry, Rachel Thompson, Ana Rath, Peter N Robinson, Hélène Dollfus, Ern-Eye Ontology Study Group

Faculty Research 2019

BACKGROUND: The optical accessibility of the eye and technological advances in ophthalmic diagnostics have put ophthalmology at the forefront of data-driven medicine. The focus of this study is rare eye disorders, a group of conditions whose clinical heterogeneity and geographic dispersion make data-driven, evidence-based practice particularly challenging. Inter-institutional collaboration and information sharing is crucial but the lack of standardised terminology poses an important barrier. Ontologies are computational tools that include sets of vocabulary terms arranged in hierarchical structures. They can be used to provide robust terminology standards and to enhance data interoperability. Here, we discuss the development of the ophthalmology-related …

Expansion Of The Human Phenotype Ontology (Hpo) Knowledge Base And Resources., Sebastian Köhler, Leigh Carmody, Nicole Vasilevsky, Julius O B Jacobsen, Daniel Danis, Jean-Philippe Gourdine, Michael Gargano, Nomi L Harris, Nicolas Matentzoglu, Julie A Mcmurry, David Osumi-Sutherland, Valentina Cipriani, James P Balhoff, Tom Conlin, Hannah Blau, Gareth Baynam, Richard Palmer, Dylan Gratian, Hugh Dawkins, Michael Segal, Anna C Jansen, Ahmed Muaz, Willie H Chang, Jenna Bergerson, Stanley J F Laulederkind, Zafer Yüksel, Sergi Beltran, Alexandra F Freeman, Panagiotis I Sergouniotis, Daniel Durkin, Andrea L Storm, Marc Hanauer, Michael Brudno, Susan M. Bello, Murat Sincan, Kayli Rageth, Matthew T Wheeler, Renske Oegema, Halima Lourghi, Maria G Della Rocca, Rachel Thompson, Francisco Castellanos, James Priest, Charlotte Cunningham-Rundles, Ayushi Hegde, Ruth C Lovering, Catherine Hajek, Annie Olry, Luigi Notarangelo, Morgan Similuk, Xingmin A Zhang, David Gómez-Andrés, Hanns Lochmüller, Hélène Dollfus, Sergio Rosenzweig, Shruti Marwaha, Ana Rath, Kathleen Sullivan, Cynthia Smith, Joshua D Milner, Dorothée Leroux, Cornelius F Boerkoel, Amy Klion, Melody C Carter, Tudor Groza, Damian Smedley, Melissa A Haendel, Chris Mungall, Peter N Robinson

Faculty Research 2019

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the …

A Contraction Stress Model Of Hypertrophic Cardiomyopathy Due To Sarcomere Mutations., Rachel Cohn, Ketan Thakar, Andre Lowe, Feria A Ladha, Anthony M Pettinato, Robert Romano, Emily Meredith, Yu-Sheng Chen, Katherine Atamanuk, Bryan D Huey, J Travis Hinson

Faculty Research 2019

Thick-filament sarcomere mutations are a common cause of hypertrophic cardiomyopathy (HCM), a disorder of heart muscle thickening associated with sudden cardiac death and heart failure, with unclear mechanisms. We engineered four isogenic induced pluripotent stem cell (iPSC) models of β-myosin heavy chain and myosin-binding protein C3 mutations, and studied iPSC-derived cardiomyocytes in cardiac microtissue assays that resemble cardiac architecture and biomechanics. All HCM mutations resulted in hypercontractility with prolonged relaxation kinetics in proportion to mutation pathogenicity, but not changes in calcium handling. RNA sequencing and expression studies of HCM models identified p53 activation, oxidative stress, and cytotoxicity induced by metabolic …

Lisa: Accurate Reconstruction Of Cell Trajectory And Pseudo-Time For Massive Single Cell Rna-Seq Data., Yang Chen, Yuping Zhang, Zhengqing Ouyang

Faculty Research 2019

Cell trajectory reconstruction based on single cell RNA sequencing is important for obtaining the landscape of different cell types and discovering cell fate transitions. Despite intense effort, analyzing massive single cell RNA-seq datasets is still challenging. We propose a new method named Landmark Isomap for Single-cell Analysis (LISA). LISA is an unsupervised approach to build cell trajectory and compute pseudo-time in the isometric embedding based on geodesic distances. The advantages of LISA include: (1) It utilizes k-nearest-neighbor graph and hierarchical clustering to identify cell clusters, peaks and valleys in low-dimension representation of the data; (2) Based on Landmark Isomap, it …

An Integrative Systems Approach Identifies Novel Candidates In Marfan Syndrome-Related Pathophysiology., Raghu Bhushan, Lukas Altinbas, Marten Jäger, Marcin Zaradzki, Daniel Lehmann, Bernd Timmermann, Nicholas P Clayton, Yunxiang Zhu, Klaus Kallenbach, Georgios Kararigas, Peter N Robinson

Faculty Research 2019

Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS-related mortality. Aberrant TGF-beta signalling plays a major role in the pathophysiology of MFS. However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta-specific pathways involved in the pathophysiology of MFS. For this purpose, we employed the Fbn1 under-expressing mgR/mgR mouse model of MFS. We performed RNA-sequencing of aortic tissues of 9-week-old mgR/mgR mice compared with wild-type (WT) mice. With …

Semantic Integration Of Clinical Laboratory Tests From Electronic Health Records For Deep Phenotyping And Biomarker Discovery., Xingmin Aaron Zhang, Amy Yates, Nicole Vasilevsky, J P Gourdine, Tiffany J Callahan, Leigh Carmody, Daniel Danis, Marcin P Joachimiak, Vida Ravanmehr, Emily R Pfaff, James Champion, Kimberly Robasky, Hao Xu, Karamarie Fecho, Nephi A Walton, Richard L Zhu, Justin Ramsdill, Christopher J Mungall, Sebastian Köhler, Melissa A Haendel, Clement J Mcdonald, Daniel J Vreeman, David B Peden, Tellen D Bennett, James A Feinstein, Blake Martin, Adrianne L Stefanski, Lawrence E Hunter, Christopher G Chute, Peter N Robinson

Faculty Research 2019

Electronic Health Record (EHR) systems typically define laboratory test results using the Laboratory Observation Identifier Names and Codes (LOINC) and can transmit them using Fast Healthcare Interoperability Resource (FHIR) standards. LOINC has not yet been semantically integrated with computational resources for phenotype analysis. Here, we provide a method for mapping LOINC-encoded laboratory test results transmitted in FHIR standards to Human Phenotype Ontology (HPO) terms. We annotated the medical implications of 2923 commonly used laboratory tests with HPO terms. Using these annotations, our software assesses laboratory test results and converts each result into an HPO term. We validated our approach with …

Representing Glycophenotypes: Semantic Unification Of Glycobiology Resources For Disease Discovery., Jean-Philippe F Gourdine, Matthew H Brush, Nicole A Vasilevsky, Kent Shefchek, Sebastian Köhler, Nicolas Matentzoglu, Monica C Munoz-Torres, Julie A Mcmurry, Xingmin Aaron Zhang, Peter N Robinson, Melissa A Haendel

Faculty Research 2019

While abnormalities related to carbohydrates (glycans) are frequent for patients with rare and undiagnosed diseases as well as in many common diseases, these glycan-related phenotypes (glycophenotypes) are not well represented in knowledge bases (KBs). If glycan-related diseases were more robustly represented and curated with glycophenotypes, these could be used for molecular phenotyping to help to realize the goals of precision medicine. Diagnosis of rare diseases by computational cross-species comparison of genotype-phenotype data has been facilitated by leveraging ontological representations of clinical phenotypes, using Human Phenotype Ontology (HPO), and model organism ontologies such as Mammalian Phenotype Ontology (MP) in the context …

High-Resolution Deconstruction Of Evolution Induced By Chemotherapy Treatments In Breast Cancer Xenografts., Hyunsoo Kim, Pooja A Kumar, Francesca Menghi, Javad Noorbakhsh, Eliza Cerveira, Mallory Ryan, Qihui Zhu, Guruprasad Ananda, Joshy George, Henry C Chen, Susan Mockus, Chengsheng Zhang, Yan Yang, James G. Keck, Radha Krishna Murthy Karuturi, Carol J Bult, Charles Lee, Edison Liu, Jeffrey H Chuang

Faculty Research 2018

The processes by which tumors evolve are essential to the efficacy of treatment, but quantitative understanding of intratumoral dynamics has been limited. Although intratumoral heterogeneity is common, quantification of evolution is difficult from clinical samples because treatment replicates cannot be performed and because matched serial samples are infrequently available. To circumvent these problems we derived and assayed large sets of human triple-negative breast cancer xenografts and cell cultures from two patients, including 86 xenografts from cyclophosphamide, doxorubicin, cisplatin, docetaxel, or vehicle treatment cohorts as well as 45 related cell cultures. We assayed these samples via exome-seq and/or high-resolution droplet digital …

Opposing Tumor-Promoting And -Suppressive Functions Of Rictor/Mtorc2 Signaling In Adult Glioma And Pediatric Shh Medulloblastoma., Seçkin Akgül, Yinghua Li, Siyuan Zheng, Marcel Kool, Daniel M Treisman, Chaoyang Li, Yuan Wang, Susanne Gröbner, Tsuneo Ikenoue, Yiping Shen, Sandra Camelo-Piragua, Gerald Tomasek, Sebastian Stark, Vinay Guduguntla, James F Gusella, Kun-Liang Guan, Stefan M Pfister, Roel G W Verhaak, Yuan Zhu

Faculty Research 2018

Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation …

Thanatomicrobiome Composition Profiling As A Tool For Forensic Investigation., Wei Zhou, Yingnan Bian

Faculty Research 2018

Thanatomicrobiome, or the postmortem microbiome, has been recognized as a useful microbial marker of the time and location of host death. In this mini-review, we compare the experimental methods commonly applied to thanatomicrobiome studies to the state-of-the-art methodologies in the microbiome field. Then, we review present findings in thanatomicrobiome studies, focusing on the diversity of the thanatomicrobiome composition and prediction models that have been proposed. Finally, we discuss potential improvements and future directions of the field.