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Busch, Evan

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Busch

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Evan

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Busch, Evan
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    Diagnostic accuracy and prediction increment of markers of epithelial-mesenchymal transition to assess cancer cell detachment from primary tumors
    (BioMed Central, 2018) Busch, Evan; Don, Prabhani Kuruppumullage; Chu, Haitao; Richardson, David B.; Keku, Temitope O.; Eberhard, David A.; Avery, Christy L.; Sandler, Robert S.
    Background: Metastases play a role in about 90% of cancer deaths. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells might provide diagnostic information about the likelihood that cancer cells have detached from the primary tumor. Used together with established diagnostic tests of detachment—lymph node evaluation and radiologic imaging—EMT marker measurements might improve the ability of clinicians to assess the patient’s risk of metastatic disease. Translation of EMT markers to clinical use has been hampered by a lack of valid analyses of clinically-informative parameters. Here, we demonstrate a rigorous approach to estimating the sensitivity, specificity, and prediction increment of an EMT marker to assess cancer cell detachment from primary tumors. Methods: We illustrate the approach using immunohistochemical measurements of the EMT marker E-cadherin in a set of colorectal primary tumors from a population-based prospective cohort in North Carolina. Bayesian latent class analysis was used to estimate sensitivity and specificity in a setting of multiple imperfect diagnostic tests and no gold standard. Risk reclassification analysis was used to assess the extent to which addition of the marker to the panel of established diagnostic tests would improve mortality prediction. We explored how changing the latent class conditional dependence assumptions and definition of marker positivity would impact the results. Results: All diagnostic accuracy and prediction increment statistics varied with the choice of cut point to define marker positivity. When comparing different definitions of marker positivity to each other, numerous trade-offs were observed in terms of sensitivity, specificity, predictive discrimination, and prediction model calibration. We then discussed several implementation considerations and the plausibility of analytic assumptions. Conclusions: The approaches presented here can be extended to any EMT marker, to most forms of cancer, and to different kinds of EMT marker measurements, such as RNA or gene methylation data. These methods provide valid, clinically-informative assessment of whether and how to use a given EMT marker to refine tumor staging and consequent treatment decisions. Electronic supplementary material The online version of this article (10.1186/s12885-017-3964-3) contains supplementary material, which is available to authorized users.
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    Pharmacogenomics Study of Thiazide Diuretics and QT Interval in Multi-Ethnic Populations: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)
    (2017) Seyerle, Amanda A; Sitlani, Colleen M; Noordam, Raymond; Gogarten, Stephanie M; Li, Jin; Li, Xiaohui; Evans, Daniel S; Sun, Fangui; Laaksonen, Maarit A; Isaacs, Aaron; Kristiansson, Kati; Highland, Heather M; Stewart, James D; Harris, Tamara B; Trompet, Stella; Bis, Joshua C; Peloso, Gina M; Brody, Jennifer A; Broer, Linda; Busch, Evan; Duan, Qing; Stilp, Adrienne M; O’Donnell, Christopher J; Macfarlane, Peter W; Floyd, James S; Kors, Jan A; Lin, Henry J; Li-Gao, Ruifang; Sofer, Tamar; Méndez-Giráldez, Raúl; Cummings, Steven R; Heckbert, Susan R; Hofman, Albert; Ford, Ian; Li, Yun; Launer, Lenore J; Porthan, Kimmo; Newton-Cheh, Christopher; Napier, Melanie D; Kerr, Kathleen F; Reiner, Alexander P; Rice, Kenneth M; Roach, Jeffrey; Buckley, Brendan M; Soliman, Elsayed Z; de Mutsert, Renée; Sotoodehnia, Nona; Uitterlinden, André G; North, Kari E; Lee, Craig R; Gudnason, Vilmundur; Stürmer, Til; Rosendaal, Frits R; Taylor, Kent D; Wiggins, Kerri L; Wilson, James G; Chen, Yii-Der I; Kaplan, Robert C; Wilhelmsen, Kirk; Cupples, L Adrienne; Salomaa, Veikko; van Duijn, Cornelia; Jukema, J Wouter; Liu, Yongmei; Mook-Kanamori, Dennis O; Lange, Leslie A; Vasan, Ramachandran S; Smith, Albert V; Stricker, Bruno H; Laurie, Cathy C; Rotter, Jerome I; Whitsel, Eric A; Psaty, Bruce M; Avery, Christy L
    Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common SNPs modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic, and cross-phenotype genome-wide analyses of European (66%), African American (15%), and Hispanic (19%) populations (N=78,199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5×10−8), we found suggestive evidence (P<5×10−6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (e.g. NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.
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    Large-scale pharmacogenomic study of sulfonylureas and the QT, JT, and QRS intervals: CHARGE Pharmacogenomics Working Group
    (2016) Floyd, James S; Sitlani, Colleen M; Avery, Christy L; Noordam, Raymond; Li, Xiaohui; Smith, Albert V; Gogarten, Stephanie M; Li, Jin; Broer, Linda; Evans, Daniel S; Trompet, Stella; Brody, Jennifer A; Stewart, James D; Eicher, John D; Seyerle, Amanda A; Roach, Jeffrey; Lange, Leslie A; Lin, Henry J; Kors, Jan A; Harris, Tamara B; Li-Gao, Ruifang; Sattar, Naveed; Cummings, Steven R; Wiggins, Kerri L; Napier, Melanie D; Stürmer, Til; Bis, Joshua C; Kerr, Kathleen F; Uitterlinden, André G; Taylor, Kent D; Stott, David J; de Mutsert, Renée; Launer, Lenore J; Busch, Evan; Méndez-Giráldez, Raúl; Sotoodehnia, Nona; Soliman, Elsayed Z; Li, Yun; Duan, Qing; Rosendaal, Frits R; Slagboom, P Eline; Wilhelmsen, Kirk C; Reiner, Alexander P; Chen, Yii-Der I; Heckbert, Susan R; Kaplan, Robert C; Rice, Kenneth M; Jukema, J Wouter; Johnson, Andrew D; Liu, Yongmei; Mook-Kanamori, Dennis O; Gudnason, Vilmundur; Wilson, James G; Rotter, Jerome I; Laurie, Cathy C; Psaty, Bruce M; Whitsel, Eric A; Cupples, L Adrienne; Stricker, Bruno H
    Sulfonylureas, a commonly-used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In eleven ethnically diverse cohorts that included 71 857 European, African American, and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT, and QRS intervals. In ancestry-specific meta-analyses, 8 novel pharmacogenomic loci met the threshold for genome-wide significance (P < 5 x 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.
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    Somatic mutations in CDH1 and CTNNB1 in primary carcinomas at 13 anatomic sites
    (Impact Journals LLC, 2017) Busch, Evan; Hornick, Jason; Umeton, Renato; Albayrak, Adem; Lindeman, Neal; MacConaill, Laura; Garcia, Elizabeth P.; Ducar, Matthew; Rebbeck, Timothy
    Metastases are involved in most cancer deaths. Evidence has suggested that cancer cell detachment from primary tumors might occur largely via the mechanism of epithelial-mesenchymal transition (EMT) activated by epigenetic events, but data addressing other possible triggers of detachment, particularly genetic mutations, have been limited. Using the Profile study of cancer genomics at Dana-Farber Cancer Institute, we examined somatic mutations in the EMT genes CDH1 in 5,106 primary carcinomas and CTNNB1 in 7,578 primary carcinomas across 13 anatomic sites: urinary bladder, breast, colon/rectum, endometrium, esophagus, kidney, lung, ovary, pancreas, prostate, skin (non-melanoma), stomach, and thyroid. For each gene and anatomic site, we calculated the prevalence of primary carcinomas with at least one mutation. Across all anatomic sites, 4% of carcinomas had at least one CDH1 mutation and 4% of carcinomas had at least one CTNNB1 mutation. By anatomic site, the observed prevalence of carcinomas with at least one mutation was less than 5% at 10 sites for CDH1 and 12 sites for CTNNB1. Tumor stage data were available for a subset of breast, colorectal, lung, and prostate tumors. Among patients from this subset who were diagnosed with regional or distant disease, only 4% had a CDH1 mutation and 1% had a CTNNB1 mutation in the primary tumor. The low mutation prevalences, especially among those with diagnoses of regional or distant disease, suggest that somatic mutations in CDH1 and CTNNB1 are unlikely to explain a substantial proportion of cancer cell detachment from primary carcinomas originating at most anatomic sites.