The Biomedical Interpretation & Training Team
Next-generation sequencing technologies have fundamentally changed the study of human genetics. Thousands of disease genes have been catalogued since the completion of the draft human genome sequencing in 2001. Genetic testing has been widely adopted as a key diagnostic tool, particularly for developmental disorders and rare genetic diseases. Despite these critical advances, our knowledge of the relationship between genotype and phenotype remains incomplete. This is evident from the fact that clinical genetic testing provides a molecular diagnosis for just 25-30% of patients referred for it.
The incredible throughput and numerous applications of high-throughput sequencing instruments holds enormous potential but also brings considerable challenges. The sheer volume of data calls for a new class of bioinformatics tools to process genomic data, as well as to identify and assess the millions of genetic variants present in all individuals to identify which ones may contribute to disease.
Our Role At IGM
The Biomedical Interpretation & Training (BIT) Team of the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital has three key responsibilities:
- Analysis & interpretation for translational research studies. These studies are applying multiple ‘omics technologies to uncover the genetic basis of conditions that affect children, particularly rare diseases, epilepsy and pediatric cancers. Using modern techniques for genomic interrogation and analysis, the lab team searches for likely-causal genetic variants patients affected by these diseases, with an emphasis on the discovery and characterization of new disease genes.
- Development of genome analysis tools. The BIT team also develops bioinformatics tools and approaches to facilitate genomic analysis and variant interpretation. These include:
- VarScan, a variant caller for next-generation sequencing data
- VaNex, a sophisticated team-based interface for variant analysis.
- Firefly, a dynamic tool for visualizing pathogenic and benign variants from ClinVar.
- Genome analysis training. The BIT team offers an embedded training program in which postdoctorial trainees, clinical fellows, and other young scientists learn to do genome analysis. They also develop presentations, documents, and other training materials.
Areas of Research
Despite the considerable advances in gene discovery and genetic testing, most patients who undergo comprehensive genetic testing (e.g. clinical exome sequencing) fail to obtain a molecular diagnosis. Such patients often continue on a diagnostic odyssey of medical testing that can last months or years without finding an answer.
Using state-of-the-art genomic approaches — whole-genome sequencing, transcriptome analysis and long-read sequencing — and innovative bioinformatics approaches, the Biomedical Informatics & Training Team identifies novel candidate genes and gene-phenotype associations in hopes of assisting patients and families in search of a diagnosis.
Congenital heart disease (CHD) is the most common birth defect and a leading cause of death in children. Understanding the genomic architecture of this condition is a clinical imperative but faces significant challenges. Genetic causes of CHD are extremely heterogeneous, comprising chromosomal anomalies (13% of cases), copy number variants (10-15%), and single-gene disorders (12%). At best, modern genetic testing provides diagnoses for 40% of patients, suggesting that many genes underlying CHD have yet to be discovered.
The COURAGE for Kids study is applying cutting-edge genomics to elucidate genetic factors that contribute to congenital heart defects and unexpected cardiac arrest in children. It will enroll hundreds of patients and their families to uncover CHD-relevant genes and their influence in long-term cardiac outcomes.
Epilepsy is one of the most common conditions associated with neurological disorders, affecting as many as 1 in 26 individuals in the United States alone. While 20-30% of cases are caused by acquired conditions (e.g. stroke, head injury or tumor), the majority are believed to have an underlying genetic etiology.
Nationwide Children’s Hospital’s Level 4 Epilepsy Center offers advanced epilepsy surgery services, including evaluation using intracranial electrodes to identify epileptogenic zones and surgical excision of affected tissue. The Biomedical Informatics & Training Team obtains excised tissue and matched normal (blood) samples from epilepsy patients for genomic study, which usually involves exome sequencing (tissue and normal samples) and RNA-seq (tissue samples), with the goal of identifying somatic variants in brain tissue that underlie disease etiology.
While the factors predisposing children to mood disorders such as depression and bipolar disorders and developmental behavior disorders like autism spectrum disorder are undoubtedly complex and varied, state-of-the-art genome sequencing of affected families may help elucidate genetic predisposition factors.
In partnership with Behavioral Health researchers at Nationwide Children’s, the Koboldt Lab is examining genomic factors influencing behavioral health with a particular focus on mood disorders in multiplex families.
Meet Our Team
Daniel C. Koboldt, MS
Principal Investigator
Dan Koboldt is a Principal Investigator at the Institute for Genomic Medicine at Nationwide Children's Hospital, and a Research Assistant Professor of Pediatrics at The Ohio State University. He is a member of the Digital Learning Committee for the American Society of Human Genetics (ASHG), and a volunteer on multiple ClinGen Variant Curation Expert Panels.
Previously, he worked as a staff scientist for the Genome Institute at Washington University, where he contributed to high-profile projects including the first cancer genome (AML1), the Cancer Genome Atlas, the 1,000 Genomes Project, and the Alzheimer's Disease Sequencing Project.
He is the developer of VarScan, a widely-used somatic mutation caller for next-generation sequencing data, and MendelScan, a variant prioritization and disease gene mapping tool for family-based sequencing studies of inherited disease.
At Nationwide Children’s, his group specializes in developing tools for the analysis and interpretation of next-generation sequencing data, particularly as applied to study rare genetic diseases in children. He is the principal investigator or a co-investigator for several translational research studies in the areas of Mendelian disorders, congenital heart disease, treatment-resistant epilepsy, congenital malformations, and other conditions.
Mohammad Marhabaie, PhD
Postdoctoral Scientist
Mohammad Marhabaie is a Senior Bioinformatics Scientist in Koboldt lab. His primary interests and responsibilities in the team are developing tools and pipelines to analyze human genetics and genomics data. He earned his B.S. in biology from the University of Isfahan in Iran, M.S. in biological science from the University of Akron in Ohio, and Ph.D. in molecular genetics from the Ohio State University. Concurrent with his undergraduate studies, he completed a three-year IT program in computer science and programming at the Aptech Computer Education Institute.
With a strong background in computer science and a deep passion for biology, he is a skilled bioinformatician who has published research studies on a broad spectrum of biological topics, including spider taxonomy, spider silk biomechanics and evolution, developmental biology, RNA-binding proteins and RNA biology, rare diseases, genomics, and human genetics.
Swetha Ramadesikan, PhD
Senior Research Scientist
Swetha Ramadesikan is a senior research scientist in the team with a strong background in functional genomics, biochemistry, and developing and in vivo and in vitro assays in studying genomic variant function. Her primary research focus is using next generation sequencing technologies including genome, somatic tissue and paired-germline exome, RNA sequencing to uncover the molecular basis for rare pediatric neurodevelopmental syndromes, congenital anomalies, and refractory epilepsy. She is also passionate about novel gene discovery in the setting of new constitutional disorders and the use of systematic reanalysis of sequencing data to improve pediatric patient outcomes. Additionally, she serves as a clinical genomic variant analyst in the IGM clinical lab.
Prior to joining the institute, she received her PhD in Biological Sciences (with a focus in cell and molecular biology) from Purdue University, West Lafayette IN where she uncovered the differential effects of genomic variants in OCRL1, a gene associated with an X-linked congenital disorder called Lowe Syndrome, in various cellular phenotypes and developed a basis for understanding the clinical heterogeneity observed in patient symptoms.
She received her bachelor’s degree in Bioengineering from SASTRA University, India. As an undergraduate she has also worked on developing biomarkers for detecting kidney injury and renal cell carcinoma at the Brigham and Women’s Hospital, Boston MA and briefly served as a cytogenetic intern at the Center for DNA Fingerprinting and Diagnostic, India.
Umamaheswaran Gurusamy, PhD
Research Scientist
Umamaheswaran Gurusamy, PhD, is a Staff Research Scientist in the Koboldt lab, where he supports genomic data analysis for translational research in behavioral health genomics and congenital heart disease. Originally from Pondicherry, India, he earned a BS in microbiology from the University of Madras, an MS in biotechnology from Bharathidasan University, and a PhD in Pharmacology from JIPMER, identifying a pharmacogenetic marker for letrozole in HR+ breast cancer. He received Junior and Senior Research Fellowships from DBT and ICMR, India, and conducted pharmacogenetic investigations on various drugs.
Dr. Gurusamy completed postdoctoral studies at Linköping University, Sweden, focusing on colorectal and breast cancer genomics, and at UCSF, where he researched complex genomic regions using optical genome mapping. His interests include OGM, PGx, and developing algorithms for integrating pharmacogenetic markers in pediatric cancer, CHD, and behavioral health disorders. In his free time, Uma enjoys cooking, playing soccer, and spending time with his kids.
Shayne Plourde, PhD
Post-doctoral Scientist (Bedrosian Lab)
Shayne Plourde, PhD, is a postdoctoral scientist on the Biomedical Informatics & Training Team. In his role he supports the analysis of genomic data from translational research protocols to identify variants responsible for a patient’s condition. He is also involved with the development of tools and pipelines to help the team analyze cases. He earned his bachelor’s degree in mathematics with a computer science minor from the University of Maine, Orono. He then came to the Ohio State University to complete a master’s in Mathematical Biosciences and then a PhD in Molecular, Cellular, and Developmental Biology. He has also completed two data science bootcamps with The Erdos Institute, once as a TA. With a strong background in mathematics, computer modeling, and biology, he is a skilled scientist with first author publications in tumor microcalcification dynamics, pollen aperture formation with Turing reaction-diffusion dynamics, and 3 compartment ODE model of C. elegans centrosome maturation.
Ashton Holub, PhD
Post-doctoral Scientist (Bedrosian Lab)
Ashton Holub, PhD, is a postdoctoral researcher in the Bedrosian lab investigating somatic mosaicism within the brain and the molecular mechanisms of epileptogenesis. He is particularly interested in the effects somatic mutations have on individual neuronal cell types. He is also a member of the Biomedical Interpretation & Training Team led by Dan Koboldt, analyzing and interpreting genomic data from multiple research protocols. Dr. Holub earned his bachelor’s degree in Biology from James Madison University and his doctorate in Molecular Genetics from The Ohio State University.
Olivia Roof
Research Intern
Olivia Roof works with Dan Koboldt’s team as a research intern learning more about human genetics and genome analysis. She is currently attending Otterbein University and plans to graduate with a Biology major and Chemistry minor. She hopes to pursue a career in genetics and continue to learn more about the field during her time at Nationwide Children's.
Contact Us
The Biomedical Interpretation & Training team is located in Research Building IV (RB4) on the main campus of Nationwide Children’s Hospital.
Mailing Address:
Dan Koboldt
700 Children’s Drive, #WC2638
Columbus, Ohio 43205
Telephone:
1-614-722-0520
E-mail: