Browsing by Author "Zhang, Jianjun"
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Item Applications of Time to Event Analysis in Clinical Data(2021-12) Xu, Chenjia; Gao, Sujuan; Liu, Hao; Zang, Yong; Zhang, Jianjun; Zhao, YiSurvival analysis has broad applications in diverse research areas. In this dissertation, we consider an innovative application of survival analysis approach to phase I dose-finding design and the modeling of multivariate survival data. In the first part of the dissertation, we apply time to event analysis in an innovative dose-finding design. To account for the unique feature of a new class of oncology drugs, T-cell engagers, we propose a phase I dose-finding method incorporating systematic intra-subject dose escalation. We utilize survival analysis approach to analyze intra-subject dose-escalation data and to identify the maximum tolerated dose. We evaluate the operating characteristics of the proposed design through simulation studies and compare it to existing methodologies. The second part of the dissertation focuses on multivariate survival data with semi-competing risks. Time-to-event data from the same subject are often correlated. In addition, semi-competing risks are sometimes present with correlated events when a terminal event can censor other non-terminal events but not vice versa. We use a semiparametric frailty model to account for the dependence between correlated survival events and semi-competing risks and adopt penalized partial likelihood (PPL) approach for parameter estimation. In addition, we investigate methods for variable selection in semi-parametric frailty models and propose a double penalized partial likelihood (DPPL) procedure for variable selection of fixed effects in frailty models. We consider two penalty functions, least absolute shrinkage and selection operator (LASSO) and smoothly clipped absolute deviation (SCAD) penalty. The proposed methods are evaluated in simulation studies and illustrated using data from Indianapolis-Ibadan Dementia Project.Item Association between Urinary Phytoestrogens and C-reactive Protein in the Continuous National Health and Nutrition Examination Survey(Taylor & Francis, 2017) Reger, Michael K.; Zollinger, Terrell W.; Liu, Ziyue; Jones, Josette; Zhang, Jianjun; Epidemiology, School of Public HealthObjective: A reduced risk of some cancers and cardiovascular disease associated with phytoestrogen intake may be mediated through its effect on serum C-reactive protein (CRP; an inflammation biomarker). Therefore, this study examined the associations between urinary phytoestrogens and serum CRP. Methods: Urinary phytoestrogen and serum CRP data obtained from 6009 participants aged ≥ 40 years in the continuous National Health and Nutrition Examination Survey during 1999–2010 were analyzed. Results: After adjustment for confounders, urinary concentrations of total and all individual phytoestrogens were inversely associated with serum concentrations of CRP (all p < 0.004). The largest reductions in serum CRP (mg/L) per interquartile range increase in urinary phytoestrogens (ng/mL) were observed for total phytoestrogens (β = −0.18; 95% confidence interval [CI], −0.22, −0.15), total lignan (β = −0.15; 95% CI, −0.18, −0.12), and enterolactone (β = −0.15; 95% CI, −0.19, −0.12). A decreased risk of having high CRP concentrations (≥3.0 mg/L) for quartile 4 vs quartile 1 was also found for total phytoestrogens (OR = 0.63; 95% CI, 0.53, 0.73), total lignan (OR = 0.64; 95% CI, 0.54, 0.75), and enterolactone (OR = 0.59; 95% CI, 0.51, 0.69). Conclusion: Urinary total and individual phytoestrogens were significantly inversely associated with serum CRP in a nationally representative sample of the U.S. population.Item Association of Plasma Aflatoxin With Persistent Detection of Oncogenic Human Papillomaviruses in Cervical Samples From Kenyan Women Enrolled in a Longitudinal Study(BMC, 2023-06-06) Tong, Yan; Tonui, Philip; Orang’o, Omenge; Zhang, Jianjun; Maina, Titus; Muthoka, Kapten; Groopman, John; Smith, Joshua; Madeen, Erin; Ermel, Aaron; Loehrer, Patrick; Brown, Darron R.; Biostatistics, School of Public HealthBackground: Cervical cancer is caused by oncogenic human papillomaviruses (HR-HPV) and is common among Kenyan women. Identification of factors that increase HR-HPV persistence is critically important. Kenyan women exposed to aflatoxin have an increased risk of HR-HPV detection in cervical specimens. This analysis was performed to examine associations between aflatoxin and HR-HPV persistence. Methods: Kenyan women were enrolled in a prospective study. The analytical cohort for this analysis included 67 HIV-uninfected women (mean age 34 years) who completed at least two of three annual study visits and had an available blood sample. Plasma aflatoxin was detected using ultra-high pressure liquid chromatography (UHPLC)-isotope dilution mass spectrometry. Annual cervical swabs were tested for HPV (Roche Linear Array). Ordinal logistic regression models were fitted to examine associations of aflatoxin and HPV persistence. Results: Aflatoxin was detected in 59.7% of women and was associated with higher risk of persistent detection of any HPV type (OR = 3.03, 95%CI = 1.08-8.55, P = 0.036), HR-HPV types (OR = 3.63, 95%CI = 1.30-10.13, P = 0.014), and HR-HPV types not included in the 9-valent HPV vaccine (OR = 4.46, 95%CI = 1.13-17.58, P = 0.032). Conclusions: Aflatoxin detection was associated with increased risk of HR-HPV persistence in Kenyan women. Further studies, including mechanistic studies are needed to determine if aflatoxin synergistically interacts with HR-HPV to increase cervical cancer risk.Item Associations between Intake of Calcium, Magnesium, and Phosphorus and Risk of Pancreatic Cancer: A Population-Based, Case-Control Study in Minnesota(Cambridge UP, 2021) Fan, Hao; Yu, Yunpeng; Nan, Haocheng; Hoyt, Margaret; Reger, Michael K.; Prizment, Anna; Anderson, Kristin E.; Zhang, Jianjun; Epidemiology, School of Public HealthExperimental studies suggest that abnormal levels of calcium, magnesium, and phosphorus are implicated in pancreatic carcinogenesis. We investigated the associations between intakes of these minerals and the risk of pancreatic cancer in a case-control study conducted in 1994-1998. Cases of pancreatic cancer (n150) were recruited from all hospitals in the metropolitan area of the Twin Cities and Mayo Clinic, Minnesota. Controls (n459) were randomly selected from the general population and frequency matched to cases by age, sex, and race. All dietary variables were adjusted for energy intake using the residual method prior to data analysis. Logistic regression was performed to evaluate the associations between intake of three nutrients examined and the risk of pancreatic cancer. Total intake of calcium (936 vs. 1026 mg/day) and dietary intake of magnesium (315 vs. 331 mg/day) and phosphorus (1350 vs. 1402 mg/day) were significantly lower in cases than in controls. After adjustment for confounders, there were not significant associations of total and dietary intakes of calcium, magnesium, and phosphorus with the risk of pancreatic cancer. In addition, no significant interactions exist between intakes of these minerals and total fat on pancreatic cancer risk. In conclusion, the present study does not suggest that intakes of calcium, magnesium, and phosphorus were significantly associated with the risk of pancreatic cancer.Item Circulating Leptin and Branched Chain Amino Acids – Correlation with Intraductal Papillary Mucinous Neoplasm Dysplastic Grade(Springer Verlag, 2019-05) Yip-Schneider, Michele T.; Simpson, Rachel; Carr, Rosalie A.; Wu, Huangbing; Fan, Hao; Liu, Ziyue; Korc, Murray; Zhang, Jianjun; Schmidt, C. Max; Surgery, School of MedicineBackground: The most common type of mucinous pancreatic cyst that may progress to pancreatic cancer is intraductal papillary mucinous neoplasm (IPMN). Low-risk IPMN with low-/moderate-grade dysplasia may be safely watched, whereas high-risk IPMN with high-grade dysplasia or invasive components should undergo resection. However, there is currently no reliable means of making this distinction. We hypothesize that blood concentrations of insulin resistance biomarkers may aid in the differentiation of low- and high-risk IPMN. Methods: Plasma/serum was collected from consented patients undergoing pancreatic resection. IPMN diagnosis and dysplastic grade were confirmed by surgical pathology. The study included 235 IPMN (166 low/moderate grade, 39 high grade, 30 invasive). Circulating levels of leptin, branched chain amino acids (BCAA), and retinol-binding protein-4 (RBP-4) were measured by enzyme-linked immunoassay and correlated with surgical pathology. Results: Circulating leptin levels (mean ± SE) were significantly higher in patients with low/moderate IPMN than in high-grade/invasive IPMN (15,803 ± 1686 vs. 10,275 ± 1228 pg/ml; p = 0.0086). Leptin levels were positively correlated with BMI (r = 0.65, p < 0.0001) and were higher in females (p < 0.0001). Stratified analysis showed that mean leptin levels were significantly different between low/moderate and high/invasive IPMNs only in females (24,383 ± 2748 vs. 16,295 ± 2040 pg/ml; p = 0.020). Conversely, circulating BCAA levels were lower in low/moderate IPMN than in high-grade/invasive IPMN (0.38 ± 0.007 vs. 0.42 ± 0.01 mM; p = 0.011). No significant differences in RBP-4 levels were observed. Conclusions: Circulating leptin in females and BCAA correlates with IPMN dysplastic grade and, if combined with clinical characteristics, have the potential to improve clinical decision-making.Item Circulating Thrombospondin-2 enhances prediction of malignant intraductal papillary mucinous neoplasm(Elsevier, 2018) Simpson, Rachel E.; Yip-Schneider, Michele T.; Wu, Huangbing; Fan, Hao; Liu, Ziyue; Korc, Murray; Zhang, Jianjun; Schmidt, C. Max; Surgery, School of MedicineBackground IPMNs are cystic pancreatic lesions with variable malignant potential. Thrombospondin-2 (THBS2)—an endogenous, anti-angiogenic matrix glycoprotein—may modulate tumor progression. We hypothesized that circulating levels of THBS2 could aid in preoperative prediction of malignant IPMN. Methods Preoperative serum/plasma samples were procured from patients undergoing surgery. Circulating levels of THBS2 were measured (enzyme-linked immunosorbent assay) and compared to surgical pathology IPMN dysplastic grade. Results 164 patients underwent THBS2 testing (100 Low/Moderate-IPMN; 64 High-Grade/Invasive-IPMN). Circulating THBS2 (mean ± SD) was greater in High-Grade/Invasive-IPMN than Low/Moderate-grade IPMN (26.6 ± 12.7 ng/mL vs. 20.4 ± 8.2 ng/mL; P < 0.001). THBS2 (AUC = 0.65) out-performed CA19-9 (n = 144; AUC = 0.59) in predicting IPMN grade. The combination of THBS2, CA19-9, radiographic main-duct involvement, main-duct diameter, age, sex, and BMI (AUC 0.82; n = 137) provided a good prediction model for IPMN grade. Conclusion Circulating THBS2 is correlated with IPMN dysplasia grade. THBS2 alone did not strongly predict IPMN grade but rather strengthened prediction models for High-Grade/Invasive IPMN when combined with other clinical/biomarker data.Item Detection and Concentration of Plasma Aflatoxin Is Associated With Detection of Oncogenic Human Papillomavirus in Kenyan Women(Oxford Academic, 2019-09-01) Zhang, Jianjun; Orang’o, Omenge; Tonui, Philip; Tong, Yan; Maina, Titus; Kiptoo, Stephen; Muthoka, Katpen; Groopman, John; Smith, Joshua; Madeen, Erin; Ermel, Aaron; Loehrer, Patrick; Brown, Darron R.; Department of Epidemiology, School of Public HealthAbstract Background Cervical cancer is common in Kenyan women. Cofactors in addition to infection with oncogenic human papillomavirus (HPV) are likely to be important in causing cervical cancer, because only a small percentage of HPV-infected women will develop this malignancy. Kenyan women are exposed to dietary aflatoxin, a potent carcinogen and immunosuppressive agent, which may be such a cofactor. Methods Demographics, behavioral data, plasma, and cervical swabs were collected from 88 human immunodeficiency virus-uninfected Kenyan women without cervical dysplasia. Human papillomavirus detection was compared between women with or without plasma aflatoxin B1-lysine (AFB1-lys) and evaluated in relation to AFB1-lys concentration. Results Valid HPV testing results were available for 86 women (mean age 34.0 years); 49 women (57.0%) had AFB1-lys detected and 37 (43.0%) had none. The AFB1-lys detection was not associated with age, being married, having more than secondary school education, home ownership, living at a walking distance to healthcare ≥60 minutes, number of lifetime sex partners, or age of first sex. The AFB1-lys detection and plasma concentrations were associated with detection of oncogenic HPV types. Conclusions The AFB1-lys positivity and higher plasma AFB1-lys concentrations were associated with higher risk of oncogenic HPV detection in cervical samples from Kenya women. Further studies are needed to determine whether aflatoxin interacts with HPV in a synergistic manner to increase the risk of cervical cancer.Item Dietary factors and risk for advanced prostate cancer(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-03) Gathirua-Mwangi, Wambui G.; Zhang, Jianjun; Department of Epidemiology, Richard M. Fairbanks School of Public HealthProstate cancer is the second most common cancer among men worldwide. Although some nutrients have been linked to the development of total prostate cancer, it remains unclear whether these nutrients modulate the risk of its clinically significant form - advanced tumor. Therefore, this study sought to perform a systematic review of the literature on this topic. The papers reviewed were identified from PubMed using keywords diet and advanced, metastatic, or lethal prostate cancer. A total of 46 papers published until September 2012 met our eligibility criteria and thus were evaluated in this review. Epidemiologic studies have shown that, overall, the habitual consumption of a diet high in saturated fat, well-done meats, and calcium is associated with an increased risk for advanced prostate cancer. An inconsistent association was observed for intake of total meat, fruits, and vegetables. Although most case-control studies suggest that intake of these nutrients or foods significantly alters advanced prostate cancer risk, cohort studies yielded mixed results. No apparent effect of fish and zinc intake on advanced prostate cancer was found in most epidemiologic studies. Epidemiologic studies conducted to date have revealed that some dietary factors modulate the risk for advanced prostate cancer. If these findings are confirmed by more adequately powered epidemiologic studies, especially prospective cohort studies that measure the nutrients and their biochemical indicators, the risk of advanced prostate cancer, which is fatal and thus clinically significant, may be reduced by dietary modification or chemoprevention.Item Dietary intake and urinary excretion of phytoestrogens in relation to cancer and cardiovascular disease(2014) Reger, Michael Kent; Zollinger, Terrell; Jones, Josette F.; Liu, Ziyue; Zhang, JianjunPhytoestrogens that abound in soy products, legumes, and chickpeas can induce biologic responses in animals and humans due to structural similarity to 17β-estradiol. Although experimental studies suggest that phytoestrogen intake may alter the risk of cancer and cardiovascular disease, few epidemiologic studies have investigated this research question. This dissertation investigated the associations of intake of total and individual phytoestrogens and their urinary biomarkers with these chronic conditions using data previously collected from two US national cohort studies (NHANES and PLCO). Utilizing NHANES data with urinary phytoestrogen concentrations and follow-up mortality, Cox proportional hazards regression (HR; 95% CI) were performed to evaluate the association between total cancer, cardiovascular disease, and all-cause mortality and urinary phytoestrogens. After adjustment for confounders, it was found that higher concentrations of lignans were associated with a reduced risk of death from cardiovascular disease (0.48; 0.24-0.97), whereas higher concentrations of isoflavones (2.14; 1.03-4.47) and daidzein (2.05; 1.02-4.11) were associated with an increased risk. A reduction in all-cause mortality was observed for elevated concentrations of lignans (0.65; 0.43-0.96) and enterolactone (0.65; 0.44-0.97). Utilizing PLCO data and dietary phytoestrogens, Cox proportional hazards regression examined the associations between dietary phytoestrogens and the risk of prostate cancer incidence. After adjustment for confounders, a positive association was found between dietary intake of isoflavones (1.58; 1.11-2.24), genistein (1.42; 1.02-1.98), daidzein (1.62; 1.13-2.32), and glycitein (1.53; 1.09-2.15) and the risk of advanced prostate cancer. Conversely, an inverse association existed between dietary intake of genistein and the risk of non-advanced prostate cancer (0.88; 0.78-0.99) and total prostate cancer (0.90; 0.81-1.00). C-reactive protein (CRP) concentration levels rise in response to inflammation and higher levels are a risk factor for some cancers and cardiovascular disease reported in epidemiologic studies. Logistic regression performed on NHANES data evaluated the association between CRP and urinary phytoestrogen concentrations. Higher concentrations of total and individual phytoestrogens were associated with lower concentrations of CRP. In summary, dietary intake of some phytoestrogens significantly modulates prostate cancer risk and cardiovascular disease mortality. It is possible that these associations may be in part mediated through the influence of phytoestrogen intake on circulating levels of C-reactive protein.Item Dietary intake of isoflavones and coumestrol and the risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial(Wiley, 2018-02) Reger, Michael K.; Zollinger, Terrell W.; Liu, Ziyue; Jones, Josette F.; Zhang, Jianjun; Epidemiology, School of Public HealthExperimental studies have revealed that phytoestrogens may modulate the risk of certain sites of cancer due to their structural similarity to 17β‐estradiol. The present study investigates whether intake of these compounds may influence prostate cancer risk in human populations. During a median follow up of 11.5 years, 2,598 cases of prostate cancer (including 287 advanced cases) have been identified among 27,004 men in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens (excluding lignans) was assessed with a food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs. Q1] was found for the dietary intake of total isoflavones [1.91 (1.25–2.92)], genistein [1.51 (1.02–2.22), daidzein [1.80 (1.18–2.75) and glycitein [1.67 (1.15–2.43)] (p‐trend for all associations ≤0.05). For example, HR (95% CI) for comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93–2.25), 1.65 (1.07–2.54), 1.73 (1.13–2.66) and 1.80 (1.18–2.75), respectively (p‐trend: 0.013). No statistically significant associations were observed between the intake of total isoflavones and individual phytoestrogens and non‐advanced and total prostate cancer after adjustment for confounders. This study revealed that dietary intake of isoflavones was associated with an elevated risk of advanced prostate cancer.