Richard J Chappell

University of Wisconsin–Madison, Madison, Wisconsin, United States

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Publications (55)254.43 Total impact

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    ABSTRACT: Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity. No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.
    Journal of Clinical Oncology 10/2013; · 17.88 Impact Factor
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    ABSTRACT: Colorectal cancer is the second leading cause of death from cancer in the United States. To facilitate the efficiency of colorectal cancer screening, there is a need to stratify risk for colorectal cancer among the 90% of US residents who are considered "average risk." In this article, we investigate such risk stratification rules for advanced colorectal neoplasia (colorectal cancer and advanced, precancerous polyps). We use a recently completed large cohort study of subjects who underwent a first screening colonoscopy. Logistic regression models have been used in the literature to estimate the risk of advanced colorectal neoplasia based on quantifiable risk factors. However, logistic regression may be prone to overfitting and instability in variable selection. Since most of the risk factors in our study have several categories, it was tempting to collapse these categories into fewer risk groups. We propose a penalized logistic regression method that automatically and simultaneously selects variables, groups categories, and estimates their coefficients by penalizing the $$L1$$-norm of both the coefficients and their differences. Hence, it encourages sparsity in the categories, i.e. grouping of the categories, and sparsity in the variables, i.e. variable selection. We apply the penalized logistic regression method to our data. The important variables are selected, with close categories simultaneously grouped, by penalized regression models with and without the interactions terms. The models are validated with 10-fold cross-validation. The receiver operating characteristic curves of the penalized regression models dominate the receiver operating characteristic curve of naive logistic regressions, indicating a superior discriminative performance.
    Statistical Methods in Medical Research 07/2013; · 2.96 Impact Factor
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    ABSTRACT: Background: Prolonged radiation treatment time (RTT) in head and neck squamous cell carcinoma (HNSCC) is associated with inferior tumor control in patients treated with radiation (RT) alone. However, the significance of prolonged RTT with concurrent chemotherapy is less clear. Methods: We reviewed outcomes for 171 patients with primary HNSCC treated with curative intent RT and concurrent drug therapy from 2001-2009. The effects of RTT and other variables on local control and survival were analyzed. Results: Patients with RTT >7 weeks had a significantly increased risk of local failure (HR 2.6; p=0.018) and death (HR 1.9 p=0.035). These results retained significance even after adjustment for tumor stage (age was not significant). Conclusions: For patients treated with concurrent radiochemotherapy, prolonged RTT may compromise tumor control as has been established in the setting of RT alone. Symptoms of HNSCC patients undergoing definitive radiochemotherapy should be managed aggressively to limit treatment interruptions. Head Neck, 2013.
    Head & Neck 06/2013; · 2.83 Impact Factor
  • Yunzhi Lin, Richard Chappell, Mithat Gönen
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    ABSTRACT: The tumor-node-metastasis (TNM) staging system has been the anchor of cancer diagnosis, treatment, and prognosis for many years. For meaningful clinical use, an orderly, progressive condensation of the T and N categories into an overall staging system needs to be defined, usually with respect to a time-to-event outcome. This can be considered as a cutpoint selection problem for a censored response partitioned with respect to two ordered categorical covariates and their interaction. The aim is to select the best grouping of the TN categories. A novel bootstrap cutpoint/model selection method is proposed for this task by maximizing bootstrap estimates of the chosen statistical criteria. The criteria are based on prognostic ability including a landmark measure of the explained variation, the area under the receiver operating characteristic (ROC) curve, and a concordance probability generalized from Harrell's c-index. We illustrate the utility of our method by applying it to the staging of colorectal cancer.
    Statistical Methods in Medical Research 05/2013; · 2.96 Impact Factor
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    ABSTRACT: Arterial stiffness may be associated with cognitive function. In this study, pulse wave velocity (PWV) was measured from the carotid to femoral (CF-PWV) and from the carotid to radial (CR-PWV) with the Complior SP System. Cognitive function was measured by 6 tests of executive function, psychomotor speed, memory, and language fluency. A total of 1433 participants were included (mean age 75 y, 43% men). Adjusting for age, sex, education, pulse rate, hemoglobin A1C, high-density lipoprotein cholesterol, hypertension, cardiovascular disease history, smoking, drinking, and depression symptoms, a CF-PWV>12 m/s was associated with a lower Mini-Mental State Examination score (coefficient: -0.31, SE: 0.11, P=0.005), fewer words recalled on Auditory Verbal Learning Test (coefficient: -1.10, SE: 0.43, P=0.01), and lower score on the composite cognition score (coefficient: -0.10, SE: 0.05, P=0.04) and marginally significantly associated with longer time to complete Trail Making Test-part B (coefficient: 6.30, SE: 3.41, P=0.06), CF-PWV was not associated with Trail Making Test-part A, Digit Symbol Substation Test, or Verbal Fluency Test. No associations were found between CR-PWV and cognitive performance measures. Higher large artery stiffness was associated with worse cognitive function, and longitudinal studies are needed to confirm these associations.
    Alzheimer disease and associated disorders 04/2013; · 2.88 Impact Factor
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    ABSTRACT: Environmental tobacco smoke (ETS) exposure has been associated with adverse health outcomes. Our goal was to determine if ETS exposure changed between 1998-2000 and 2003-2005 among participants in the population-based Epidemiology of Hearing Loss Study. ETS exposure was ascertained using a cotinine-validated questionnaire at the 5-year (1998-2000) and 10-year follow-up examinations (2003-2005). Non-smoking participants with data from both visits were included (n=1898; ages 53-96 years at 5-yr follow-up). McNemar's test was used to test differences in ETS exposure overall and in 3 settings: home, work, and social settings. Generalized estimating equations (GEE) were used for multivariate logistic regression models of exposure. The proportion of nonsmokers with no or little ETS exposure increased from 80% to 88% (P< 0.0001). The percent living in a home with no indoor smokers increased from 94% to 97% (P<0.0001). The percent reporting no exposure at work increased from 91% to 95% (P<0.0001). The percent reporting the lowest frequency of social exposure increased from 65% to 77% (P<0.0001). In the GEE model, age was inversely associated with overall ETS exposure (Odds Ratio [OR] per 5 yr= 0.87, 95% CI= 0.81, 0.94), as was education (OR for college vs < high school=0.25, 95% CI=0.16, 0.37), female gender (ORI= 0.41, 95% CI= 0.33, 0.51), and later examination period (OR =0.62, 95% CI= 0.53, 0.73); current employment was positively associated with exposure (OR=1.44, 95% CI=1.14, 1.83). Between the late 1990s and the mid-2000s, ETS exposure in older adults decreased. Decreasing exposures suggest there may be future declines in ETS-related adverse health outcomes.
    WMJ: official publication of the State Medical Society of Wisconsin 04/2013; 112(2):53-7.
  • Yunzhi Lin, Sijian Wang, Richard J Chappell
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    ABSTRACT: The tumor-node-metastasis staging system has been the lynchpin of cancer diagnosis, treatment, and prognosis for many years. For meaningful clinical use, an orderly grouping of the T and N categories into a staging system needs to be defined, usually with respect to a time-to-event outcome. This can be reframed as a model selection problem with respect to features arranged on a partially ordered two-way grid, and a penalized regression method is proposed for selecting the optimal grouping. Instead of penalizing the L1-norm of the coefficients like lasso, in order to enforce the stage grouping, we place L1 constraints on the differences between neighboring coefficients. The underlying mechanism is the sparsity-enforcing property of the L1 penalty, which forces some estimated coefficients to be the same and hence leads to stage grouping. Partial ordering constraints is also required as both the T and N categories are ordinal. A series of optimal groupings with different numbers of stages can be obtained by varying the tuning parameter, which gives a tree-like structure offering a visual aid on how the groupings are progressively made. We hence call the proposed method the lasso tree. We illustrate the utility of our method by applying it to the staging of colorectal cancer using survival outcomes. Simulation studies are carried out to examine the finite sample performance of the selection procedure. We demonstrate that the lasso tree is able to give the right grouping with moderate sample size, is stable with regard to changes in the data, and is not affected by random censoring.
    Biostatistics 12/2012; · 2.24 Impact Factor
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    ABSTRACT: Carotid atherosclerosis has been suggested to be involved in cognitive decline. The Epidemiology of Hearing Loss Study is a longitudinal study of aging among Beaver Dam residents, WI. In 1998-2000, carotid intima-media thickness (IMT) and plaque were measured by ultrasound; cognitive function was measured by the Mini-Mental State Examination (MMSE). Follow-up examinations were conducted in 2003-2005 and 2009-2010. Incidence of cognitive impairment was defined as an MMSE score <24 or reported physician-diagnosed dementia during the follow-up. In the last examination, five additional cognitive tests were added. The associations of carotid atherosclerosis with incident cognitive impairment and cognitive test performance ten years later were evaluated. A total of 1651 participants (mean age 66.8 years, 41% men) without cognitive impairment at baseline were included in the incidence analysis. IMT was associated with incidence of cognitive impairment after multiple adjustments (hazard ratio: 1.09, p = 0.02 for each 0.1 mm increase in IMT). A total of 1311 participants with atherosclerosis data at baseline had the additional cognitive tests 10 years later. Larger IMT was associated with longer time to complete the Trail-Making Test-part B after multiple adjustments (0.1 mm IMT: 2.3 s longer, p = 0.02). Plaque was not associated with incident cognitive impairment or cognitive test performance 10 years later. In this population-based longitudinal study, carotid IMT was associated with a higher risk of developing cognitive impairment during the 10-year follow-up, and was associated with poorer performance in a test of executive function 10 years later.
    Atherosclerosis 07/2012; 224(2):506-10. · 3.71 Impact Factor
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    ABSTRACT: The purpose of our study was to compare setup variation in four degrees of freedom (vertical, longitudinal, lateral, and roll) between canine nasal tumor patients immobilized with a mattress and bite block, versus a mattress alone. Our secondary aim was to define a clinical target volume (CTV) to planning target volume (PTV) expansion margin based on our mean systematic error values associated with nasal tumor patients immobilized by a mattress and bite block. We evaluated six parameters for setup corrections: systematic error, random error, patient-patient variation in systematic errors, the magnitude of patient-specific random errors (root mean square [RMS]), distance error, and the variation of setup corrections from zero shift. The variations in all parameters were statistically smaller in the group immobilized by a mattress and bite block. The mean setup corrections in the mattress and bite block group ranged from 0.91 mm to 1.59 mm for the translational errors and 0.5°. Although most veterinary radiation facilities do not have access to Image-guided radiotherapy (IGRT), we identified a need for more rigid fixation, established the value of adding IGRT to veterinary radiation therapy, and define the CTV-PTV setup error margin for canine nasal tumor patients immobilized in a mattress and bite block.
    Veterinary Radiology &amp Ultrasound 06/2012; 53(4):474-81. · 1.26 Impact Factor
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    ABSTRACT: PURPOSE: To quantify associations between pre-radiotherapy and post-radiotherapy PET parameters via spatially resolved regression. MATERIALS AND METHODS: Ten canine sinonasal cancer patients underwent PET/CT scans of [(18)F]FDG (FDG(pre)), [(18)F]FLT (FLT(pre)), and [(61)Cu]Cu-ATSM (Cu-ATSM(pre)). Following radiotherapy regimens of 50Gy in 10 fractions, veterinary patients underwent FDG PET/CT scans at 3months (FDG(post)). Regression of standardized uptake values in baseline FDG(pre), FLT(pre) and Cu-ATSM(pre) tumour voxels to those in FDG(post) images was performed for linear, log-linear, generalized-linear and mixed-fit linear models. Goodness-of-fit in regression coefficients was assessed by R(2). Hypothesis testing of coefficients over the patient population was performed. RESULTS: Multivariate linear model fits of FDG(pre) to FDG(post) were significantly positive over the population (FDG(post)∼0.17·FDG(pre), p=0.03), and classified slopes of RECIST non-responders and responders to be different (0.37 vs. 0.07, p=0.01). Generalized-linear model fits related FDG(pre) to FDG(post) by a linear power law (FDG(post)∼FDG(pre)(0.93),p<0.001). Univariate mixture model fits of FDG(pre) improved R(2) from 0.17 to 0.52. Neither baseline FLT PET nor Cu-ATSM PET uptake contributed statistically significant multivariate regression coefficients. CONCLUSIONS: Spatially resolved regression analysis indicates that pre-treatment FDG PET uptake is most strongly associated with three-month post-treatment FDG PET uptake in this patient population, though associations are histopathology-dependent.
    Radiotherapy and Oncology 06/2012; · 4.86 Impact Factor
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    ABSTRACT: Background/Aims: Hypercholesterolemia in midlife increases risk for Alzheimer's disease (AD) and contributes to cerebrovascular dysregulation - an early finding in preclinical AD pathology. Statins improve vascular reactivity, but it is unknown if they increase regional cerebral blood flow (CBF) in individuals at risk for AD. Methods: In a randomized, controlled, double-blind pilot study, 16 asymptomatic middle-aged adults with parental history of AD were randomized to atorvastatin or placebo daily for 4 months. At baseline and month 4, regional CBF was measured using arterial spin-labeling magnetic resonance imaging and endothelial function was measured using brachial artery ultrasound. Results: At baseline, participants with low HDL-cholesterol, higher global vascular risk, and greater endothelial dysfunction had reduced regional CBF in areas of the brain related to memory and learning (all p < 0.03). Using voxel-based analysis, 4 months of atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to placebo. Conclusion: In this pilot study, atorvastatin increased regional CBF in persons at risk for AD. Further research is warranted to confirm whether statins increase CBF in areas of the brain related to memory and learning and whether such perfusion changes are associated with a delay in the onset of AD. Clinical Trial Registration: Identifier: NCT00751907.
    Current Alzheimer research 11/2011; 9(8):990-7. · 4.97 Impact Factor
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    ABSTRACT: This study's objective was to quantify the impact (utility) of common complications of early cervical cancer treatment on quality of life (QOL). Utilities assigned by survivors were compared to those assigned by providers. 30 survivors of early cervical cancer identified from our Tumor Registry and 10 gynecologic oncology providers were interviewed. Participants evaluated complications (health states) using the standard gamble (SG) and visual analogue scale (VAS). Each participant was randomly assigned to rate 5 of 13 health states. Mixed-effects linear models were used to generate confidence intervals for utility means, and evaluate the effect of group (survivors versus providers). Higher utilities indicate the health state is closer to perfect health. Survivors and providers mean ages were similar (44 and 40). Mean time from diagnosis was 6.7 years. 28 of 30 survivors had no evidence of disease. 56% of survivors had complications. Using SG, providers consistently assigned utilities 7% higher than survivors (p=0.035) for all health states except "ileostomy", which survivors rated higher than providers. Survivors assigned the lowest utility to small bowel obstruction (SBO) (fixable without an ostomy) and ureteral obstruction (UO). Survivors rated SBO 16% and UO 21% lower than providers. Personal history of complications or higher stage did not have a consistent effect on QOL adjustments. Providers assign higher utilities than survivors to health states. Providers and survivors diverge on which complications impact QOL the most. Data on patient preferences should be considered when weighing treatment options with similar survival but different associated complications.
    Gynecologic Oncology 11/2011; 125(1):163-7. · 3.69 Impact Factor
  • Fuel and Energy Abstracts 10/2011; 81(2).
  • Fuel and Energy Abstracts 10/2011; 81(2).
  • Medical Physics 01/2011; 38(6):3742-. · 3.01 Impact Factor
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    ABSTRACT: To investigate the relationships between lifestyle behaviors of diet, smoking, and physical activity and the subsequent prevalence of age-related macular degeneration (AMD). The population included 1313 participants (aged 55-74 years) in the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative Observational Study. Scores on a modified 2005 Healthy Eating Index were assigned using responses to a food frequency questionnaire administered at baseline of the Women's Health Initiative Observational Study (1994-1998). Physical activity and lifetime smoking history were queried. An average of 6 years later, stereoscopic fundus photographs were taken to assess the presence and severity of AMD; it was present in 202 women, 94% of whom had early AMD, the primary outcome. In multivariate models, women whose diets scored in the highest quintile compared with the lowest quintile on the modified 2005 Healthy Eating Index had 46% lower odds for early AMD. Women in the highest quintile compared with those in the lowest quintile for physical activity (in metabolic energy task hours per week) had 54% lower odds for early AMD. Although smoking was not independently associated with AMD on its own, having a combination of 3 healthy behaviors (healthy diet, physical activity, and not smoking) was associated with 71% lower odds for AMD compared with having high-risk scores (P < .001). Modifying lifestyles might reduce risk for early AMD as much as 3-fold, lowering the risk for advanced AMD in a person's lifetime and the social and economic costs of AMD to society.
    Archives of ophthalmology 12/2010; 129(4):470-80. · 3.86 Impact Factor
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    ABSTRACT: Intensity-modulated radiation therapy (IMRT) allows optimization of radiation dose delivery to complex tumor volumes with rapid dose drop-off to surrounding normal tissues. A prospective study was performed to evaluate the concept of conformal avoidance using IMRT in canine sinonasal cancer. The potential of IMRT to improve clinical outcome with respect to acute and late ocular toxicity was evaluated. Thirty-one dogs with sinonasal cancer were treated definitively with IMRT using helical tomotherapy and/or dynamic multileaf collimator (DMLC) delivery. Ocular toxicity was evaluated prospectively and compared with a comparable group of historical controls treated with conventional two-dimensional radiotherapy (2D-RT) techniques. Treatment plans were devised for each dog using helical tomotherapy and DMLC that achieved the target dose to the planning treatment volume and limited critical normal tissues to the prescribed dose-volume constraints. Overall acute and late toxicities were limited and minor, detectable by an experienced observer. This was in contrast to the profound ocular morbidity observed in the historical control group treated with 2D-RT. Overall median survival for IMRT-treated and 2D-treated dogs was 420 and 411 days, respectively. Compared with conventional techniques, IMRT reduced dose delivered to eyes and resulted in bilateral ocular sparing in the dogs reported herein. These data provide proof-of-principle that conformal avoidance radiotherapy can be delivered through high conformity IMRT, resulting in decreased normal tissue toxicity as compared with historical controls treated with 2D-RT.
    Veterinary Radiology &amp Ultrasound 09/2010; 51(5):561-70. · 1.26 Impact Factor
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    ABSTRACT: To assess the association between healthy diet scores and prevalence of nuclear cataract in women. The association between healthy diet scores, which reflect adherence to the US dietary guidelines, and prevalence of nuclear cataract determined 4 to 7 years later was assessed in a sample of Women's Health Initiative Observational Study participants (aged 50-79 years) residing in Iowa, Wisconsin, and Oregon. Scores on the 1995 Healthy Eating Index, which reflect adherence to 1990 guidelines, were assigned from responses to food frequency questionnaires at the Women's Health Initiative baseline (1994-1998). Presence of nuclear cataract was determined from slitlamp photographs and self-reports of cataract extractions were assessed from May 1, 2001, to January 31, 2004, in 1808 women participating in the Carotenoids in Age-Related Eye Disease Study. Having a high 1995 Healthy Eating Index score was the strongest modifiable predictor of low prevalence of nuclear cataract among numerous risk factors investigated in this sample. The multivariate-adjusted odds ratio for high vs low quintile for diet score was 0.63 (95% confidence interval, 0.43-0.91). Higher prevalence of nuclear cataract was also associated with other modifiable factors (smoking and marked obesity) and nonmodifiable factors (having brown eyes, myopia, and high pulse pressure). Vitamin supplement use was not related to cataract. These data add to the body of evidence suggesting that eating foods rich in a variety of vitamins and minerals may contribute to postponing the occurrence of the most common type of cataract in the United States.
    Archives of ophthalmology 06/2010; 128(6):738-49. · 3.86 Impact Factor
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    ABSTRACT: To evaluate the relationships between the amount and type of dietary fat and intermediate age-related macular degeneration (AMD). Women aged 50 to 79 years with high and low lutein intake from 3 sites of the Women's Health Initiative Observational Study were recruited into the Carotenoids in Age-Related Eye Disease Study. Fat intake from 1994 through 1998 was estimated using food frequency questionnaires, and AMD was assessed photographically from 2001 through 2004. Intakes of omega-6 and omega-3 polyunsaturated fatty acids, which were highly correlated (r = 0.8), were associated with approximately 2-fold higher prevalence of intermediate AMD in high vs low quintiles. However, monounsaturated fatty acid intake was associated with lower prevalence. Age interactions were often observed. In women younger than 75 years (n = 1325), total fat and saturated fatty acid intakes were associated with increased prevalence of AMD (multivariate adjusted odds ratios [95% confidence interval] for intermediate AMD, 1.7 [1.0-2.7] for quintile 5 vs quintile 1 for total fat [P = .10 for trend] and 1.6 [0.7-3.6] for saturated fatty acids [P = .23 for trend]). The associations were reversed in older women. These results support a growing body of evidence suggesting that diets high in several types of fat may contribute to the risk of intermediate AMD and that diets high in monounsaturated fatty acids may be protective.
    Archives of ophthalmology 11/2009; 127(11):1483-93. · 3.86 Impact Factor
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    R Drees, L J Forrest, R Chappell
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    ABSTRACT: Canine intranasal neoplasia is commonly evaluated using computed tomography to indicate the diagnosis, to determine disease extent, to guide histological sampling location and to plan treatment. With the expanding use of magnetic resonance imaging in veterinary medicine, this modality has been recently applied for the same purpose. The aim of this study was to compare the features of canine intranasal neoplasia using computed tomography and magnetic resonance imaging. Twenty-one dogs with confirmed intranasal neoplasia underwent both computed tomography and magnetic resonance imaging. The images were reviewed retrospectively for the bony and soft tissue features of intranasal neoplasia. Overall computed tomography and magnetic resonance imaging performed very similarly. However, lysis of bones bordering the nasal cavity and mucosal thickening was found on computed tomography images more often than on magnetic resonance images. Small amounts of fluid in the nasal cavity were more often seen on magnetic resonance images. However, fluid in the frontal sinuses was seen equally well with both modalities. We conclude that computed tomography is satisfactory for evaluation of canine intranasal neoplasia, and no clinically relevant benefit is gained using magnetic resonance imaging for intranasal neoplasia without extent into the cranial cavity.
    Journal of Small Animal Practice 07/2009; 50(7):334-40. · 0.91 Impact Factor

Publication Stats

2k Citations
254.43 Total Impact Points


  • 1994–2012
    • University of Wisconsin–Madison
      • • Department of Biostatistics and Medical Informatics
      • • Department of Medicine
      • • Department of Ophthalmology and Visual Sciences
      • • Department of Human Oncology
      • • Department of Statistics
      Madison, Wisconsin, United States
  • 2009
    • CUNY Graduate Center
      New York City, New York, United States
  • 2007
    • Rutgers New Jersey Medical School
      • Cancer Institute of New Jersey
      Newark, NJ, United States