Multivariate Data Analysis with Applications to Cancer

Multivariate data is common in a wide range of settings. As data structures become increasingly complex, additional statistical tools are required to perform proper analyses. In this dissertation we develop and evaluate methods for the analysis of multivariate data generated from cancer trials. In the first chapter we consider the analysis of clustered survival data that can arise from multicenter clinical trials. In particular, we review and compare marginal and conditional models numerically through simulations and discuss model selection techniques. A multicenter clinical trial of children with acute lymphoblastic leukemia is used to illustrate the findings. The second and third chapters both address the setting where multiple outcomes are collected when the outcome of interest cannot be measured directly. A head and neck cancer trial in which multiple outcomes were collected to measure dysphagia was the particular motivation for this part of the dissertation. Specifically, in the second chapter we propose a semiparametric latent variable transformation model that incorporates measurable outcomes of mixed types, including censored outcomes. This method extends traditional approaches by allowing the relationship between the measurable outcomes and latent variable to be unspecified, rendering more robust inference. Using this approach we can directly estimate the treatment (or other covariate) effect on the unobserved latent variable, enhancing interpretation. In the third chapter, the basic model from the second chapter is maintained, but additional parametric assumptions are made. This model still has the advantages of allowing for censored measurable outcomes and being able to estimate a treatment effect on the latent variable, but has the added advantage of good performance in a small data set. Together the methods proposed in the second and third chapters provide a comprehensive approach for the analysis of complex multiple outcomes data

Who presents satisfied? Non-modifiable factors associated with patient satisfaction among gynecologic oncology clinic patients

To examine associations between non-modifiable patient factors and patient satisfaction (PS) among women presenting to a gynecologic oncology clinic

The health-related quality of life journey of gynecologic oncology surgical patients: Implications for the incorporation of patient-reported outcomes into surgical quality metrics

To report the changes in patient-reported quality of life for women undergoing gynecologic oncology surgeries

Chemotherapy and Stem Cell Transplantation Increase p16

AbstractThe expression of markers of cellular senescence increases exponentially in multiple tissues with aging. Age-related physiological changes may contribute to adverse outcomes in cancer survivors. To investigate the impact of high dose chemotherapy and stem cell transplantation on senescence markers in vivo, we collected blood and clinical data from a cohort of 63 patients undergoing hematopoietic cell transplantation. The expression of p16INK4a, a well-established senescence marker, was determined in T-cells before and 6months after transplant. RNA sequencing was performed on paired samples from 8 patients pre- and post-cancer therapy. In patients undergoing allogeneic transplant, higher pre-transplant p16INK4a expression was associated with a greater number of prior cycles of chemotherapy received (p=0.003), prior autologous transplantation (p=0.01) and prior exposure to alkylating agents (p=0.01). Transplantation was associated with a marked increase in p16INK4a expression 6months following transplantation. Patients receiving autologous transplant experienced a larger increase in p16INK4a expression (3.1-fold increase, p=0.002) than allogeneic transplant recipients (1.9-fold increase, p=0.0004). RNA sequencing of T-cells pre- and post- autologous transplant or cytotoxic chemotherapy demonstrated increased expression of transcripts associated with cellular senescence and physiological aging. Cytotoxic chemotherapy, especially alkylating agents, and stem cell transplantation strongly accelerate expression of a biomarker of molecular aging in T-cells

The impact of surgical complications on health-related quality of life in women undergoing gynecologic and gynecologic oncology procedures: a prospective longitudinal cohort study

There are currently no assessments of the impact of surgical complications on health-related quality of life in gynecology and gynecologic oncology. This is despite complications being a central focus of surgical outcome measurement, and an increasing awareness of the need for patient-reported data when measuring surgical quality

Success of Endoscopic Pharyngoesophageal Dilation after Head and Neck Cancer Treatment

To assess clinical success and safety of endoscopic pharyngoesophageal dilation after chemoradiation or radiation for head and neck cancer and to identify variables associated with dilation failure

Use of mobile device technology to continuously collect patient-reported symptoms during radiation therapy for head and neck cancer: A prospective feasibility study

AbstractPurposeAccurate assessment of toxicity allows for timely delivery of supportive measures during radiation therapy for head and neck cancer. The current paradigm requires weekly evaluation of patients by a provider. The purpose of this study is to evaluate the feasibility of monitoring patient reported symptoms via mobile devices.Methods and materialsWe developed a mobile application for patients to report symptoms in 5 domains using validated questions. Patients were asked to report symptoms using a mobile device once daily during treatment or more often as needed. Clinicians reviewed patient-reported symptoms during weekly symptom management visits and patients completed surveys regarding perceptions of the utility of the mobile application. The primary outcome measure was patient compliance with mobile device reporting. Compliance is defined as number of days with a symptom report divided by number of days on study.ResultsThere were 921 symptom reports collected from 22 patients during treatment. Median reporting compliance was 71% (interquartile range, 45%-80%). Median number of reports submitted per patient was 34 (interquartile range, 21-53). Median number of reports submitted by patients per week was similar throughout radiation therapy and there was significant reporting during nonclinic hours. Patients reported high satisfaction with the use of mobile devices to report symptoms.ConclusionsA substantial percentage of patients used mobile devices to continuously report symptoms throughout a course of radiation therapy for head and neck cancer. Future studies should evaluate the impact of mobile device symptom reporting on improving patient outcomes

Prognostic Value of Teratoma in Primary Tumor and Postchemotherapy Retroperitoneal Lymph Node Dissection Specimens in Patients With Metastatic Germ Cell Tumor

Purpose: Presence of teratoma in patients with metastatic testicular germ cell tumor (GCT) is of unknown prognostic significance. We report survival outcomes of patients with or without teratoma in primary tumor and postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) specimen and assess impact on prognosis. Patients and methods: Patients with metastatic nonseminomatous GCT (NSGCT) who were evaluated at Indiana University between 1990 and 2016 and had primary testicular tumor specimen from orchiectomy (ORCH) were included. All patients were treated with cisplatin-based combination chemotherapy. The cohort was divided into 2 groups according to presence or absence of teratoma in ORCH specimen. Survival data were correlated with histopathologic findings. Differences in progression-free (PFS) and overall survival (OS) were evaluated using log-rank tests and Cox proportional hazards models to adjust for known adverse prognostic factors. Results: We identified 1,224 consecutive patients evaluated at Indiana University between 1990 and 2016 who met inclusion criteria. Median age was 27 years (range, 13-71 years); 689 patients had teratoma in ORCH specimen, and 535 did not. With median follow-up of 2.3 years, 5-year PFS was 61.9% (95% CI, 57.1% to 66.2%) for those with teratoma versus 63.1% (95% CI, 58.0% to 67.8%) for those without (P = .66); 5-year OS was 82.2% (95% CI, 77.9% to 85.8%) versus 81.4% (95% CI, 76.5% to 85.3%; P = .91), respectively. A total of 473 patients underwent PC-RPLND; 5-year PFS for patients with pure teratoma in PC-RPLND specimen versus necrosis only was 65.9% versus 79.1% (P = .06), and 5-year OS was 90.3% versus 93.4% (P = .21), respectively. Conclusion: Presence of teratoma in ORCH and PC-RPLND specimens was not a prognostic factor in this large retrospective study of patients with NSGCT

Chemotherapy and Stem Cell Transplantation Increase p16INK4a Expression, a Biomarker of T-cell Aging

The expression of markers of cellular senescence increases exponentially in multiple tissues with aging. Age-related physiological changes may contribute to adverse outcomes in cancer survivors. To investigate the impact of high dose chemotherapy and stem cell transplantation on senescence markers in vivo, we collected blood and clinical data from a cohort of 63 patients undergoing hematopoietic cell transplantation. The expression of p16INK4a, a well-established senescence marker, was determined in T-cells before and 6 months after transplant. RNA sequencing was performed on paired samples from 8 patients pre- and post-cancer therapy. In patients undergoing allogeneic transplant, higher pre-transplant p16INK4a expression was associated with a greater number of prior cycles of chemotherapy received (p = 0.003), prior autologous transplantation (p = 0.01) and prior exposure to alkylating agents (p = 0.01). Transplantation was associated with a marked increase in p16INK4a expression 6 months following transplantation. Patients receiving autologous transplant experienced a larger increase in p16INK4a expression (3.1-fold increase, p = 0.002) than allogeneic transplant recipients (1.9-fold increase, p = 0.0004). RNA sequencing of T-cells pre- and post- autologous transplant or cytotoxic chemotherapy demonstrated increased expression of transcripts associated with cellular senescence and physiological aging. Cytotoxic chemotherapy, especially alkylating agents, and stem cell transplantation strongly accelerate expression of a biomarker of molecular aging in T-cells