Browsing by Author "Hyslop, Terry"
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Item Open Access Characterizing chronological accumulation of comorbidities in healthy veterans: a computational approach.(Scientific reports, 2021-04-14) Hong, Julian C; Hauser, Elizabeth R; Redding, Thomas S; Sims, Kellie J; Gellad, Ziad F; O'Leary, Meghan C; Hyslop, Terry; Madison, Ashton N; Qin, Xuejun; Weiss, David; Bullard, A Jasmine; Williams, Christina D; Sullivan, Brian A; Lieberman, David; Provenzale, DawnUnderstanding patient accumulation of comorbidities can facilitate healthcare strategy and personalized preventative care. We applied a directed network graph to electronic health record (EHR) data and characterized comorbidities in a cohort of healthy veterans undergoing screening colonoscopy. The Veterans Affairs Cooperative Studies Program #380 was a prospective longitudinal study of screening and surveillance colonoscopy. We identified initial instances of three-digit ICD-9 diagnoses for participants with at least 5 years of linked EHR history (October 1999 to December 2015). For diagnoses affecting at least 10% of patients, we calculated pairwise chronological relative risk (RR). iGraph was used to produce directed graphs of comorbidities with RR > 1, as well as summary statistics, key diseases, and communities. A directed graph based on 2210 patients visualized longitudinal development of comorbidities. Top hub (preceding) diseases included ischemic heart disease, inflammatory and toxic neuropathy, and diabetes. Top authority (subsequent) diagnoses were acute kidney failure and hypertensive chronic kidney failure. Four communities of correlated comorbidities were identified. Close analysis of top hub and authority diagnoses demonstrated known relationships, correlated sequelae, and novel hypotheses. Directed network graphs portray chronologic comorbidity relationships. We identified relationships between comorbid diagnoses in this aging veteran cohort. This may direct healthcare prioritization and personalized care.Item Open Access Clinical and pathological stage discordance among 433,514 breast cancer patients.(American journal of surgery, 2019-10) Plichta, Jennifer K; Thomas, Samantha M; Sergesketter, Amanda R; Greenup, Rachel A; Fayanju, Oluwadamilola M; Rosenberger, Laura H; Tamirisa, Nina; Hyslop, Terry; Hwang, E ShelleyBACKGROUND:We aim to determine clinical and pathological stage discordance rates and to evaluate factors associated with discordance. METHODS:Adults with clinical stages I-III breast cancer were identified from the National Cancer Data Base. Concordance was defined as cTN = pTN (discordance: cTN≠pTN). Multivariate logistic regression was used to identify factors associated with discordance. RESULTS:Comparing clinical and pathological stage, 23.1% were downstaged and 8.7% were upstaged. After adjustment, factors associated with downstaging (vs concordance) included grade 3 (OR 10.56, vs grade 1) and HER2-negative (OR 3.79). Factors associated with upstaging (vs concordance) were grade 3 (OR 10.56, vs grade 1), HER2-negative (OR 1.25), and lobular histology (OR 2.47, vs ductal). ER-negative status was associated with stage concordance (vs downstaged or upstaged, OR 0.52 and 0.87). CONCLUSIONS:Among breast cancer patients, nearly one-third exhibit clinical-pathological stage discordance. This high likelihood of discordance is important to consider for counseling and treatment planning.Item Open Access Component-wise gradient boosting and false discovery control in survival analysis with high-dimensional covariates.(Bioinformatics, 2016-01-01) He, Kevin; Li, Yanming; Zhu, Ji; Liu, Hongliang; Lee, Jeffrey E; Amos, Christopher I; Hyslop, Terry; Jin, Jiashun; Lin, Huazhen; Wei, Qinyi; Li, YiMOTIVATION: Technological advances that allow routine identification of high-dimensional risk factors have led to high demand for statistical techniques that enable full utilization of these rich sources of information for genetics studies. Variable selection for censored outcome data as well as control of false discoveries (i.e. inclusion of irrelevant variables) in the presence of high-dimensional predictors present serious challenges. This article develops a computationally feasible method based on boosting and stability selection. Specifically, we modified the component-wise gradient boosting to improve the computational feasibility and introduced random permutation in stability selection for controlling false discoveries. RESULTS: We have proposed a high-dimensional variable selection method by incorporating stability selection to control false discovery. Comparisons between the proposed method and the commonly used univariate and Lasso approaches for variable selection reveal that the proposed method yields fewer false discoveries. The proposed method is applied to study the associations of 2339 common single-nucleotide polymorphisms (SNPs) with overall survival among cutaneous melanoma (CM) patients. The results have confirmed that BRCA2 pathway SNPs are likely to be associated with overall survival, as reported by previous literature. Moreover, we have identified several new Fanconi anemia (FA) pathway SNPs that are likely to modulate survival of CM patients. AVAILABILITY AND IMPLEMENTATION: The related source code and documents are freely available at https://sites.google.com/site/bestumich/issues. CONTACT: yili@umich.edu.Item Embargo Exposomic modeling approaches for social and environmental determinants of health(2023) McCormack, KaraStudies of human health have recently expanded to focus on the exposome paradigm, encompassing allexposures humans encounter from conception onward. The central theme of this work is to develop and test novel statistical methodologies that can address the challenges of the complex relationships between environmental exposures, socioeconomic distress, and health outcomes. However, source, measurement, and volume intricacies inherent to these data have constrained progression of statistical methods for key research questions.
In this work, we explore three approaches to characterizing community health and its potential impact on several types of disease outcomes. In the first approach, we implement a latent class model to socioeconomic and comorbidities data and explore these classifications as fixed effects in an ecological spatial model of COVID-19 cases and deaths in NYC during two time periods of the pandemic. In the second, we use a non-parametric Bayesian approach to form socio-economic and pollution cluster profiles across US counties. We then use these profiles to inform a Bayesian spatial model on breast cancer mortality for data from 2014. In the final approach, we utilize a latent network model traditionally used in psychometrics research to explore structural racism. Using information from five domains (employment, education, housing, health, and criminal justice), we identify new variable complexes to illustrate the complex the manifestations of structural racism at the census tract level in Pennsylvania.
Item Open Access Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival.(Molecular carcinogenesis, 2018-01) Xu, Yinghui; Wang, Yanru; Liu, Hongliang; Shi, Qiong; Zhu, Dakai; Amos, Christopher I; Fang, Shenying; Lee, Jeffrey E; Hyslop, Terry; Li, Xin; Han, Jiali; Wei, QingyiMetzincins are key molecules in the degradation of the extracellular matrix and play an important role in cellular processes such as cell migration, adhesion, and cell fusion of malignant tumors, including cutaneous melanoma (CM). We hypothesized that genetic variants of the metzincin metallopeptidase family genes would be associated with CM-specific survival (CMSS). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate the associations between genetic variants of 75 metzincin metallopeptidase family genes and CMSS using the dataset from the genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC) which included 858 non-Hispanic white patients with CM, and then validated using the dataset from the Harvard GWAS study which had 409 non-Hispanic white patients with invasive CM. Four independent SNPs (MMP16 rs10090371 C>A, ADAMTS3 rs788935 T>C, TLL2 rs10882807 T>C and MMP9 rs3918251 A>G) were identified as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) of 1.73 (1.32-2.29, 9.68E-05), 1.46 (1.15-1.85, 0.002), 1.68 (1.31-2.14, 3.32E-05) and 0.67 (0.51-0.87, 0.003), respectively, in the meta-analysis of these two GWAS studies. Combined analysis of risk genotypes of these four SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (Ptrend < 0.001). An improvement was observed in the prediction model (area under the curve [AUC] = 81.4% vs. 78.6%), when these risk genotypes were added to the model containing non-genotyping variables. Our findings suggest that these genetic variants may be promising prognostic biomarkers for CMSS.Item Open Access Nodal Response to Neoadjuvant Chemotherapy Predicts Receipt of Radiation Therapy after Breast Cancer Diagnosis.(International journal of radiation oncology, biology, physics, 2019-10-31) Fayanju, Oluwadamilola M; Ren, Yi; Suneja, Gita; Thomas, Samantha M; Greenup, Rachel A; Plichta, Jennifer K; Rosenberger, Laura H; Force, Jeremy; Hyslop, Terry; Hwang, E ShelleyBACKGROUND:Pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with improved overall survival (OS) in breast-cancer patients, but it is unclear how post-NACT response influences radiotherapy administration in patients presenting with node-positive disease. We sought to determine whether nodal pCR is associated with likelihood of receiving nodal radiation and whether radiotherapy among patients experiencing nodal pCR is associated with improved OS. METHODS:cN1 female breast cancer patients diagnosed 2010-2015 who were ypN0 (i.e., nodal pCR, n=12,341) or ypN1 (i.e., residual disease, n=13,668) post-NACT were identified in the National Cancer Database. Multivariate logistic regression was used to identify factors associated with receiving radiotherapy. Cox proportional hazards modeling was used to estimate the association between radiotherapy and adjusted OS. RESULTS:26,009 patients were included. 43.9% (n=5,423) of ypN0 and 55.3% (n=7,556) of ypN1 patients received nodal radiation. Rates of nodal radiation remained the same over time among ypN0 patients (trend test p=0.29) but increased among ypN1 patients from 49% in 2010 to 59% in 2015 (trend test p<0.001). After adjusting for covariates, nodal pCR (vs no stage change) was associated with decreased likelihood of nodal radiation after mastectomy (∼20% decrease) and lumpectomy (∼30% decrease, both p<0.01). After mastectomy, nodal (vs no) radiation conferred no significant survival benefit in ypN0 patients but approached significance for ypN1 patients (hazard ratio [HR] 0.83, 95% CI 0.69-0.99, p=0.04, overall p-value=0.11). After lumpectomy, nodal radiation was associated with improved adjusted OS for ypN0 (HR 0.38, 95% CI 0.22-0.66) and ypN1 patients (HR 0.44, 95% CI 0.30-0.66, both p<0.001), but this improvement was not significantly greater than that associated with breast-only radiation. CONCLUSIONS:ypN0 patients were less likely to receive nodal radiation than ypN1 patients, suggesting that selective omission already occurs and, in the context of limited survival data, could potentially be appropriate for select patients.Item Open Access Single-nucleotide polymorphisms of stemness genes predicted to regulate RNA splicing, microRNA and oncogenic signaling are associated with prostate cancer survival.(Carcinogenesis, 2018-07) Freedman, Jennifer A; Wang, Yanru; Li, Xuechan; Liu, Hongliang; Moorman, Patricia G; George, Daniel J; Lee, Norman H; Hyslop, Terry; Wei, Qingyi; Patierno, Steven RProstate cancer (PCa) is a clinically and molecularly heterogeneous disease, with variation in outcomes only partially predicted by grade and stage. Additional tools to distinguish indolent from aggressive disease are needed. Phenotypic characteristics of stemness correlate with poor cancer prognosis. Given this correlation, we identified single-nucleotide polymorphisms (SNPs) of stemness-related genes and examined their associations with PCa survival. SNPs within stemness-related genes were analyzed for association with overall survival of PCa in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Significant SNPs predicted to be functional were selected for linkage disequilibrium analysis and combined and stratified analyses. Identified SNPs were evaluated for association with gene expression. SNPs of CD44 (rs9666607), ABCC1 (rs35605 and rs212091) and GDF15 (rs1058587) were associated with PCa survival and predicted to be functional. A role for rs9666607 of CD44 and rs35605 of ABCC1 in RNA splicing regulation, rs212091 of ABCC1 in miRNA binding site activity and rs1058587 of GDF15 in causing an amino acid change was predicted. These SNPs represent potential novel prognostic markers for overall survival of PCa and support a contribution of the stemness pathway to PCa patient outcome.Item Open Access The impact of chemotherapy sequence on survival in node-positive invasive lobular carcinoma.(Journal of surgical oncology, 2019-08) Tamirisa, Nina; Williamson, Hannah V; Thomas, Samantha M; Westbrook, Kelly E; Greenup, Rachel A; Plichta, Jennifer K; Rosenberger, Laura H; Hyslop, Terry; Hwang, Eun-Sil Shelley; Fayanju, Oluwadamilola MBACKGROUND AND OBJECTIVES:We sought to evaluate the impact of chemotherapy sequence on survival by comparing node-positive invasive lobular carcinoma (ILC) patients who received neoadjuvant (NACT) and adjuvant (ACT) chemotherapy. METHODS:cT1-4c, cN1-3 ILC patients in the National Cancer Data Base (2004-2013) who underwent surgery and chemotherapy were divided into NACT and ACT cohorts. Kaplan-Meier curves and Cox proportional hazards modeling were used to estimate unadjusted and adjusted overall survival (OS), respectively. RESULTS:Five thousand five hundred fifty-one (35.6%) of 15 573 ILC patients treated with chemotherapy received NACT. NACT patients had similar rates of pT3/4 disease (26.6% vs 26.2%), nodal involvement (median 3 vs 4), and number of lymph nodes examined (median 13 vs 14) but higher rates of mastectomy (81.8% vs 74.5%, P < 0.001) vs ACT patients. 3.4% of NACT patients experienced pathologic complete response (pCR). Unadjusted 10-year OS was worse for NACT vs ACT patients (65.1% vs 54.4%, log-rank P < 0.001). After adjustment for known covariates, NACT continued to be associated with worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.25-1.52). CONCLUSIONS:In node-positive ILC, NACT yielded low rates of pCR, was not associated with lower rates of mastectomy or less extensive axillary surgery, and was associated with worse survival vs ACT, suggesting limited benefit for these patients.Item Open Access The Influence of Age on the Histopathology and Prognosis of Atypical Breast Lesions.(The Journal of surgical research, 2019-09) Sergesketter, Amanda R; Thomas, Samantha M; Fayanju, Oluwadamilola M; Menendez, Carolyn S; Rosenberger, Laura H; Greenup, Rachel A; Hyslop, Terry; Parrilla Castellar, Edgardo R; Hwang, E Shelley; Plichta, Jennifer KBACKGROUND:Although several prognostic variables and risk factors for breast cancer are age-related, the association between age and risk of cancer with breast atypia is controversial. This study aimed to compare the type of breast atypia and risk of underlying or subsequent breast cancer by age. METHODS:Adult women with breast atypia (atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ) at a single institution from 2008 to 2017 were stratified by age at initial diagnosis: <50 y, 50-70 y, and >70 y. Regression modeling was used to estimate the association of age with risk of underlying carcinoma or subsequent cancer diagnosis. RESULTS:A total of 530 patients with atypia were identified: 31.1% < 50 y (n = 165), 58.1% 50-70 y (n = 308), and 10.8% > 70 y (n = 57). The proportion of women with atypical ductal hyperplasia steadily increased with age, compared with atypical lobular proliferations (P = 0.04). Of those with atypia on needle biopsy, the overall rate of underlying carcinoma was 17.5%. After adjustment, older age was associated with a greater risk of underlying carcinoma (odds ratio: 1.028, 95% confidence interval: 1.003-1.053; P = 0.03). Of those confirmed to have atypia on surgical excision, the overall rate of a subsequent cancer diagnosis was 15.7%. Age was not associated with a long-term risk for breast cancer (P = 0.48) or the time to a subsequent diagnosis of carcinoma (log-rank P = 0.41). CONCLUSIONS:Although atypia diagnosed on needle biopsy may be sufficient to warrant surgical excision, older women may be at a greater risk for an underlying carcinoma, albeit the long-term risk for malignancy associated with atypia does not appear to be affected by age.Item Open Access Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study.(Clinical cancer research : an official journal of the American Association for Cancer Research, 2019-01-11) Crosby, Erika J; Gwin, William; Blackwell, Kimberly; Marcom, Paul K; Chang, Serena; Maecker, Holden T; Broadwater, Gloria; Hyslop, Terry; Kim, Sungjin; Rogatko, Andre; Lubkov, Veronica; Snyder, Joshua C; Osada, Takuya; Hobeika, Amy C; Morse, Michael A; Lyerly, H Kim; Hartman, Zachary CPURPOSE:Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T cell infiltration of tumors include vaccines targeting established oncogenic drivers like the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). EXPERIMENTAL DESIGN:In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were evaluated. We tested VRP-HER2 in a Phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of three doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. RESULTS:Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was one partial response and two patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n=4) and 32.7 months in cohort 2 (n=18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. CONCLUSIONS:VRP-HER2 increased HER2-specific memory CD8 T cells and had anti-tumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T cell activity by combining with anti-PD-1.