Program: Molecular Genetics and Genomics
Current advisor: Obi L. Griffith, PhD
Undergraduate university: Cornell University
Precision oncology has been adopted as the ideal paradigm for optimization of outcomes for patients with cancer. However, the application of precision oncology to every clinical workflow has been unattainable. Suboptimal adoption of custom medicine within oncology is attributable to the annotation bottleneck, which currently demands inordinate manual and computational requirements for completion. Alleviation of the annotation bottleneck requires co-development of bioinformatic strategies and analysis knowledgebanks to automate variant identification and variant annotation for clinical use. My research provides methods and examples of alleviation of the annotation bottleneck within the precision oncology pipeline. This includes the development of three tools (OpenCAP, DeepSVR, and a manual review Standard Operating Procedure) that improve upon existing methods for variant identification and annotation. The Open-sourced CIViC Annotation Pipeline (OpenCAP) serves as a software to create rationally designed clinical capture panels that are linked to clinical relevance summaries to improve library preparation and clinical annotation. DeepSVR provides a machine learning approach to improve automated somatic variant calling by reducing false positives associated with sequencing pipelines that are observable by manual reviewers. The manual review Standard Operating Procedure provides a systemic and standardized approach for manual review of aligned sequencing reads for sequencing data with paired tumor and normal samples. The combined utility of these three tools for alleviation of the analysis bottleneck was demonstrated using the MyeloSeq targeted capture panel, which evaluates recurrent mutations observed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
Beyond research conducted under Dr. Obi Griffith, I am also developing a multi-target stool RNA diagnostic to assess for colorectal neoplasias in average-risk individual between the ages of 45-75. This diagnostic (ColonoSight) has received Breakthrough Device Designation from the FDA for its novel ability to detect adenomas with high sensitivity and specificity. The most recent clinical trial (n = 1,327 patients) demonstrated 95% sensitivity for colorectal cancer, 100% sensitivity for high-grade dysplasia / carcinoma in-situ, and 62% sensitivity for advanced adenomas with 85% specificity for no findings on a colonoscopy. Currently, a 8,500-patient Phase III clinical trial is ongoing to support a pre-market approval application to the FDA with expected completion in June of 2022.
Krysiak K, Danos AM, Kiwala S, McMichael JF, Coffman AC, Barnell EK, Sheta L, Saliba J, Grisdale CJ, Kujan L, Pema S, Lever J, Spies NC, Chiorean A, Rieke DT, Clark KA, Jani P, Takahashi H, Horak P, Ritter DI, Zhou X, Ainscough BJ, Delong S, Lamping M, Marr AR, Li BV, Lin WH, Terraf P, Salama Y, Campbell KM, Farncombe KM, Ji J, Zhao X, Xu X, Kanagal-Shamanna R, Cotto KC, Skidmore ZL, Walker JR, Zhang J, Milosavljevic A, Patel RY, Giles RH, K. 2022 A community approach to the cancer-variant-interpretation bottleneck. Nat Cancer, 3(5):522-25.
Krysiak K, Danos AM, Saliba J, McMichael JF, Coffman AC, Kiwala S, Barnell EK, Sheta L, Grisdale CJ, Kujan L, Pema S, Lever J, Ridd S, Spies NC, Andric V, Chiorean A, Rieke DT, Clark KA, Reisle C, Venigalla AC, Evans M, Jani P, Takahashi H, Suda A, Horak P, Ritter DI, Zhou X, Ainscough BJ, Delong S, Kesserwan C, Lamping M, Shen H, Marr AR, Hoang MH, Singhal K, Khanfar M, Li BV, Lin WH, Terraf P, Corson LB, Salama Y, Campbell KM, Farncombe KM, Ji J, Zhao X, Xu X, Kanagal-Shamanna R, King I, Cotto KC, Skidmore ZL, Walker JR, Zhang J, Milosavljevic A, Patel RY, Giles RH, Kim RH, Schriml LM, Mardis ER, Jones SJM, Raca G, Rao S, Madhavan S, Wagner AH, Griffith M, Griffith OL. 2022 CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase. Nucleic Acids Res, ():Online ahead of print.
Barnell EK, Newcomer KF, Skidmore ZL, Krysiak K, Anderson SR, Wartman LD, Oh ST, Welch JS, Stockerl-Goldstein KE, Vij R, Cashen AF, Pusic I, Westervelt P, Abboud CN, Ghobadi A, Uy GL, Schroeder MA, Dipersio JF, Politi MC, Spencer DH, Duncavage EJ, Ley TJ, Griffith M, Jacoby MA, Griffith OL. 2021 Impact of a 40-Gene Targeted Panel Test on Physician Decision Making for Patients With Acute Myeloid Leukemia. JCO Precis Oncol, 5():PO.20.00182.
Mudianto T, Campbell KM, Webb J, Zolkind P, Skidmore ZL, Riley R, Barnell EK, Ozgenc I, Giri T, Dunn GP, Adkins DR, Griffith M, Egloff AM, Griffith OL, Uppaluri R. 2021 Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas. Clin Cancer Res, ():Online ahead of print.
Wagner AH, Kiwala S, Coffman AC, McMichael JF, Cotto KC, Mooney TB, Barnell EK, Krysiak K, Danos AM, Walker J, Griffith OL, Griffith M. 2020 CIViCpy: A Python Software Development and Analysis Toolkit for the CIViC Knowledgebase. JCO Clin Cancer Inform, 4():245-53.
Uppaluri R, Campbell KM, Egloff AM, Zolkind P, Skidmore ZL, Nussenbaum B, Paniello RC, Rich JT, Jackson R, Pipkorn P, Michel LS, Ley J, Oppelt P, Dunn GP, Barnell EK, Spies NC, Lin T, Li T, Mulder D, Hanna Y, Cirlan I, Pugh TJ, Mudianto T, Riley R, Zhou L, Jo VY, Stachler MD, Hanna GJ, Kass JI, Haddad RI, Schoenfeld JD, Gjini E, Lako A, Thorstad WL, Gay HA, Daly M, Rodig S, Hagemann IS, Kallogjeri D, Piccirillo JF, Chernock RD, Griffith M, Griffith OL, Adkins DR. 2020 Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase 2 Trial. Clin Cancer Res, ():clincanres.1695.2020.
Danos AM, Krysiak K, Barnell EK, Coffman AC, McMichael JF, Kiwala S, Spies NC, Sheta LM, Pema SP, Kujan L, Clark KA, Wollam AZ, Rao S, Ritter DI, Sonkin D, Raca G, Lin WH, Grisdale CJ, Kim RH, Wagner AH, Madhavan S, Griffith M, Griffith OL. 2019 Standard operating procedure for curation and clinical interpretation of variants in cancer. Genome Med, 11(7):76.
Barnell EK, Ronning P, Campbell KM, Krysiak K, Ainscough BJ, Sheta LM, Pema SP, Schmidt AD, Richters M, Cotto KC, Danos AM, Ramirez C, Skidmore ZL, Spies NC, Hundal J, Sediqzad MS, Kunisaki J, Gomez F, Trani L, Matlock M, Wagner AH, Swamidass SJ, Griffith M, Griffith OL. 2019 Standard operating procedure for somatic variant refinement of sequencing data with paired tumor and normal samples. Genet Med, 21(4):972-981.
Campbell KM, O’Leary KA, Rugowski DE, Mulligan WA, Barnell EK, Skidmore ZL, Krysiak K, Griffith M, Schuler LA, Griffith OL. 2019 A Spontaneous Aggressive ERα+ Mammary Tumor Model Is Driven by Kras Activation. Cell Rep, 28(6):1526-1537.e4.
Barnell EK, Waalkes A, Mosior MC, Penewit K, Cotto KC, Danos AM, Sheta LM, Campbell KM, Krysiak K, Rieke D, Spies NC, Skidmore ZL, Pritchard CC, Fehniger TA, Uppaluri R, Govindan R, Griffith M, Salipante SJ, Griffith OL. 2019 Open-Sourced CIViC Annotation Pipeline to Identify and Annotate Clinically Relevant Variants Using Single-Molecule Molecular Inversion Probes. JCO Clin Cancer Inform, 3():1-12.
Barnell EK, Kang Y, Wurtzler EM, Griffith M, Chaudhuri AA, Griffith OL; Geneoscopy Scientists. 2019 Noninvasive Detection of High-Risk Adenomas Using Stool-Derived Eukaryotic RNA Sequences as Biomarkers. Gastroenterology, 157(3):884-87.
Campbell KM, Lin T, Zolkind P, Barnell EK, Skidmore ZL, Winkler AE, Law JH, Mardis ER, Wartman LD, Adkins DR, Chernock RD, Griffith M, Uppaluri R, Griffith OL. 2018 Oral Cavity Squamous Cell Carcinoma Xenografts Retain Complex Genotypes and Intertumor Molecular Heterogeneity. Cell Rep, 24(8):2167-2178.
Barnell EK, Kang Y, Campbell KM, Barnell A, Wurtzler EM. (2018) Pre-clinical performance of stool RNA for detection of adenomas and colorectal cancer. Digestive Disease Week Annual Meeting, Washington, DC, Abstract.
Barnell EK. (2018) Deep learning approach to automate somatic variant refinement. 66th Annual Meeting of The American Society of Human Genetics, San Diego, CA, Abstract.
Ainscough BJ, Barnell EK, Ronning P, Campbell KM, Wagner AH, Fehniger TA, Dunn GP, Uppaluri R, Govindan R, Rohan TE, Griffith M, Mardis ER, Swamidass SJ, Griffith OL. 2018 A deep learning approach to automate refinement of somatic variant calling from cancer sequencing data. Nat Genet, 50():1735-43.
Danos AM, Ritter DI, Wagner AH, Krysiak K, Sonkin D, Micheel C, McCoy M, Rao S, Raca G, Boca SM, Roy A, Barnell EK, McMichael JF, Kiwala S, Coffman AC, Kujan L, Kulkarni S, Griffith M, Madhavan S, Griffith OL. 2018 Adapting crowdsourced clinical cancer curation in CIViC to the ClinGen minimum variant level data community-driven standards. Hum Mutat, 39(11):1721-1732.
Griffith M, Spies NC, Krysiak K, McMichael JF, Coffman AC, Danos AM, Ainscough BJ, Ramirez CA, Rieke DT, Kujan L, Barnell EK, Wagner AH, Skidmore ZL, Wollam A, Liu CJ, Jones MR, Bilski RL, Lesurf R, Feng YY, Shah NM, Bonakdar M, Trani L, Matlock M, Ramu A, Campbell KM, Spies GC, Graubert AP, Gangavarapu K, Eldred JM, Larson DE, Walker JR, Good BM, Wu C, Su AI, Dienstmann R, Margolin AA, Tamborero D, Lopez-Bigas N, Jones SJM, Bose R, Spencer DH, WartmanLD, Wilson RK, Mardis ER, Griffith OL. 2017 CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer. Nat Genet, 49(2):170-174.
Ma CX, Suman V, Goetz MP, Northfelt D, Burkard ME, Ademuyiwa F, Naughton M, Margenthaler J, Aft R, Gray R, Tevaarwerk A, Wilke L, Haddad T, Moynihan T, Loprinzi C, Hieken T, Barnell EK, Skidmore ZL, Feng YY, Krysiak K, Hoog J, Guo Z, Nehring L, Wisinski KB, Mardis E, Hagemann IS, Vij K, Sanati S, Al-Kateb H, Griffith OL, Griffith M, Doyle L, Erlichman C, Ellis MJ. 2017 A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III PIK3CA-Mutant ER-Positive and HER2-Negative Breast Cancer. Clin Cancer Res, 23(22):6823-6832.
Barnell EK. (2017) Development and validation of a cancer variant capture panel using the open-access CIViC database. American Assocaition for Cancer Research, Washington, DC, Abstract.
Yu J, Ordiz MI, Stauber J, Shaikh N, Trehan I, Barnell E, Head RD, Maleta K, Tarr PI, Manary MJ. 2015 Environmental Enteric Dysfunction Includes a Broad Spectrum of Inflammatory Responses and Epithelial Repair Processes. Cell Mol Gastroenterol Hepatol, 2(2):158-174.e1.