New Statistical Methods for Phase I Clinical Trials of a Single Agent

The primary goal of phase I clinical trials in oncology is to determine a safe and possibly effective dose of a treatment, and to recommend this dose for further testing in larger trials. With chemotherapeutic treatments, the risk of severe dose-limiting toxicity (DLT) is the primary concern, assuming that the probability of efficacy will necessarily increase with dose. A phase I trial then seeks the highest dose with acceptable risk of DLT, called the maximum tolerated dose (MTD). Increasing the dose beyond the MTD would lead to unacceptable risk, while decreasing the dose would decrease the probability of benefit. In contrast, many newer therapies are molecularly targeted, where the probabilities of DLT and efficacy may plateau or even rise and then fall after some threshold. In this setting, a phase I trial must account for both toxicity and efficacy in identifying an optimal dose. In this dissertation, we present three new approaches to modeling data in phase I trials of a single agent. Our methods improve on current practice by making more use of commonly available data. First, for chemotherapies, we investigate the utility of counting multiple DLTs per patient, in addition to counting lower-level toxicities (LLT). Typically, methods for phase I trials model only binary DLT responses, and ignore LLTs. We find that using event counts and including LLTs increases the probability of correctly identifying the MTD, particularly when the MTD is not among the highest dose levels being considered. Second, we consider chemotherapies that are administered over multiple cycles, where dosage may vary across cycles. Multi-cycle treatments are often analyzed using only DLTs observed in the first cycle, ignoring DLTs from later cycles and thus potentially underestimating the DLT rates. We develop a latent process model, representing a continuous level of toxicity over time, which rises and falls after each administration, but which is only observed discretely in each cycle as either no toxicity, LLT, or DLT. The process is inspired by the pharmacokinetics of drug absorption and clearance. We use our model to re-estimate the MTD at the end of adaptive trials that originally used only first-cycle data, and we find that our model typically increases the probability of correctly identifying the MTD. Our method can also recommend how to adjust a patient's dose mid-treatment, to attain a target DLT rate. Third, we develop a method for molecularly targeted therapies, incorporating both DLTs and efficacy responses and allowing the rates of both responses to vary flexibly with dose. In particular, we adopt the conditional autoregressive model, which allows us to share information between dose levels without imposing any functional form on the dose-response curves. We find that our method can adapt to a variety of dose-toxicity and dose-efficacy patterns, and often performs at least as well as competing methods.PHDBiostatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/140847/1/dmuenz_1.pd

Conditional Survival in Patients with Thyroid Cancer

Background: Thyroid cancer is an increasingly common malignancy. Although likelihood of survival from well-differentiated thyroid cancer can vary by disease severity, it is not known how patients' life expectancies change the farther they are from time of diagnosis. Methods: Using data from the Surveillance, Epidemiology, End Results (SEER) registry, we selected patients diagnosed with well-differentiated thyroid cancer (N=43,392) between 1998 and 2005. Patients were followed for up to 12 years. Conditional survival estimates by SEER stage and age were obtained based on Cox proportional hazards regression model of disease-specific survival. Results: Patients with localized thyroid cancer have excellent conditional 5-year survival, irrespective of where they are in their survivorship phase. Patients with regional thyroid cancer have relatively stable conditional 5-year survival, whereas for patients with distant thyroid cancer there is gradual improvement the farther from time of diagnosis. Age and gender influence conditional survival. Similarly, age has a strong effect on disease-specific survival for patients with thyroid cancer with localized (hazard ratio [HR] 88.7 [95% confidence interval {CI} 26.3?552), comparing age ≥80 with <30 years), regional (HR 105 [95% CI 52.6?250]), and distant disease [HR 86.8 (95% CI 32.5?354)]. Male gender is also associated with a significantly worse disease-specific survival among patients with regional disease (HR 1.56 [95% CI 1.31?1.85]) but not among patients with localized or distant disease. Conclusion: Cancer stage, gender, age at diagnosis, and length of time already survived can influence conditional survival for patients with thyroid cancer. Understanding the conditional 5-year disease-specific survival of well-differentiated thyroid cancer is key to creating treatment plans and tailoring surveillance.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140260/1/thy.2014.0264.pd

Does drug‐induced sleep endoscopy predict surgical success in transoral robotic multilevel surgery in obstructive sleep apnea?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136419/1/lary26255_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136419/2/lary26255.pd

Association between aerobic fitness and the functional connectome in patients with schizophrenia

BACKGROUND: Schizophrenia is accompanied by widespread alterations in static functional connectivity associated with symptom severity and cognitive deficits. Improvements in aerobic fitness have been demonstrated to ameliorate symptomatology and cognition in people with schizophrenia, but the intermediary role of macroscale connectivity patterns remains unknown. OBJECTIVE: Therefore, we aim to explore the relation between aerobic fitness and the functional connectome in individuals with schizophrenia. Further, we investigate clinical and cognitive relevance of the identified fitness-connectivity links. METHODS: Patients diagnosed with schizophrenia were included in this cross-sectional resting-state fMRI analysis. Multilevel Bayesian partial correlations between aerobic fitness and functional connections across the whole brain as well as between static functional connectivity patterns and clinical and cognitive outcome were performed. Preliminary causal inferences were enabled based on mediation analyses. RESULTS: Static functional connectivity between the subcortical nuclei and the cerebellum as well as between temporal seeds mediated the attenuating relation between aerobic fitness and total symptom severity. Functional connections between cerebellar seeds affected the positive link between aerobic fitness and global cognition, while the functional interplay between central and limbic seeds drove the beneficial association between aerobic fitness and emotion recognition. CONCLUSION: The current study provides first insights into the interactions between aerobic fitness, the functional connectome and clinical and cognitive outcome in people with schizophrenia, but causal interpretations are preliminary. Further interventional aerobic exercise studies are needed to replicate the current findings and to enable conclusive causal inferences. TRIAL REGISTRATION: The study which the manuscript is based on is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00406-022-01411-x

Outcome Prediction in Patients with Severe COVID-19 Requiring Extracorporeal Membrane Oxygenation—A Retrospective International Multicenter Study

The role of veno-venous extracorporeal membrane oxygenation therapy (V-V ECMO) in severe COVID-19 acute respiratory distress syndrome (ARDS) is still under debate and conclusive data from large cohorts are scarce. Furthermore, criteria for the selection of patients that benefit most from this highly invasive and resource-demanding therapy are yet to be defined. In this study, we assess survival in an international multicenter cohort of COVID-19 patients treated with V-V ECMO and evaluate the performance of several clinical scores to predict 30-day survival. Methods: This is an investigator-initiated retrospective non-interventional international multicenter registry study (NCT04405973, first registered 28 May 2020). In 127 patients treated with V-V ECMO at 15 centers in Germany, Switzerland, Italy, Belgium, and the United States, we calculated the Sequential Organ Failure Assessment (SOFA) Score, Simplified Acute Physiology Score II (SAPS II), Acute Physiology And Chronic Health Evaluation II (APACHE II) Score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) Score, Predicting Death for Severe ARDS on V-V ECMO (PRESERVE) Score, and 30-day survival. Results: In our study cohort which enrolled 127 patients, overall 30-day survival was 54%. Median SOFA, SAPS II, APACHE II, RESP, and PRESERVE were 9, 36, 17, 1, and 4, respectively. The prognostic accuracy for all these scores (area under the receiver operating characteristic—AUROC) ranged between 0.548 and 0.605. Conclusions: The use of scores for the prediction of mortality cannot be recommended for treatment decisions in severe COVID-19 ARDS undergoing V-V ECMO; nevertheless, scoring results below or above a specific cut-off value may be considered as an additional tool in the evaluation of prognosis. Survival rates in this cohort of COVID-19 patients treated with V-V ECMO were slightly lower than those reported in non-COVID-19 ARDS patients treated with V-V ECMO

Missed Opportunities for Prevention of Mother-to-Child Transmission of Human Immunodeficiency Virus

OBJECTIVE:To identify missed opportunities for prevention of mother-to-child transmission of human immunodeficiency virus (HIV). METHODS:Data regarding HIV-infected children born between 2002 and 2009 to HIV-infected women enrolled in the U.S. International Maternal Pediatric Adolescent AIDS Clinical Trials prospective cohort study (protocol P1025) were reviewed. The characteristics of the HIV-infected infants and their mothers and the mothersʼ clinical management are described. RESULTS:Twelve cases of mother-to-child transmission of HIV occurred among 1,857 liveborn neonates, for a prevalence of 0.65 per 100 live births to HIV-infected women (95% confidence interval 0.33–1.13). Four transmissions occurred in utero, three were peripartum transmissions, and the timing of transmission for five neonates was unable to be determined. None were breastfed. Seven women had plasma viral loads greater than 400 copies/mL near delivery. Six women had less than 11 weeks of antiretroviral therapy during pregnancy; three of these women had premature deliveries. One woman received no antiretroviral therapy during pregnancy because she was diagnosed with HIV postpartum. Six had poor to moderate adherence to antiretroviral therapy. Four of the five mothers with viral loads greater than 1,000 copies/mL delivered preterm neonates. There were five women who delivered by cesarean; four were nonelective cesarean deliveries and only one was an elective cesarean delivery for HIV prevention. CONCLUSION:Despite access to high-level care and follow-up, a small proportion of HIV-infected women transmitted the virus to their neonates. This case series provides insight into factors contributing to HIV perinatal transmission and can inform the development of new strategies for prevention of mother-to-child transmission of HIV. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, https://clinicaltrials.gov, NCT00028145

Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals

Although use of efficacious interventions, including antiretrovirals (ARVs), has dramatically reduced the rate of mother-to-child transmission of human immunodeficiency virus, the safety of in utero ARV exposure remains of concern. Data regarding 1112 infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 born between 2002 and 2007 were analyzed for this study. Congenital anomalies were classified based on the Metropolitan Atlanta Congenital Defects Program guidelines. Associations between congenital anomalies and timing of first in utero exposure to ARVs were evaluated by logistic regression analysis. Congenital anomalies were identified and confirmed in 61 of the 1112 infants, resulting in a prevalence of 5.49/100 live births (95% confidence interval, 4.22-6.99). Among the 80 anomalies identified, the organ systems involved included cardiovascular (n = 33), musculoskeletal (n = 15), renal (n = 9), genitourinary (n = 6), craniofacial (n = 4), and central nervous system (n = 2). First trimester exposure to efavirenz was associated with a significantly increased risk of congenital anomalies (odds ratio, 2.84; 95% confidence interval, 1.13-7.16). No significant associations were observed between exposure to other individual ARVs or classes of ARVs started at any time during pregnancy and infant congenital anomalies. The observed rate of congenital anomalies in this cohort is higher than previously reported for the general population, but it is consistent with rates observed in other recent studies of children born to human immunodeficiency virus-infected women. Cardiovascular anomalies occurred most frequently. With the exception of a known teratogen (efavirenz), no statistically significant associations between in utero exposure to ARVs and congenital anomalies were identified

Tumor Biomarkers in Spindle Cell Variant Squamous Cell Carcinoma of the Head and Neck

OBJECTIVE: To determine biomarkers of recurrence and survival in patients with spindle cell variant squamous cell carcinoma (SpSCC) of the head and neck. STUDY DESIGN: Retrospective case control study. SETTING: Tertiary academic center. SUBJECTS AND METHODS: Thirty-two SpSCC patients (mean age, 68.8) between 1987 and 2009 were identified and reviewed. A tissue microarray (TMA) was constructed from tumor specimens. Tumor biomarkers under study included p16, EGFR, p53, EZH2, Cyclin D1, CD104, HGFa, p21, and cMET. An additional TMA was constructed from patients with non-SpSCC oral cavity squamous cell carcinoma for comparative purposes. The main outcomes were overall survival (OS), disease specific survival (DSS) and recurrence free survival (RFS). RESULTS: In the SpSCC cohort, tumors positive for cMet had worse OS (p<0.001). Patients positive for cMet (p=0.007), Cyclin D1 (p=0.019), and p16 (p=0.004) had worse DSS. RFS was also worse in patients with tumors positive for cMet (p=0.037), Cyclin D1 (p=0.012), and p16 (p<0.001). Compared to the oral cavity cohort there was a significantly larger proportion of patients in the SpSCC group with tumors staining positive for cMet and a lower proportion of tumors positive for cyclin D1. CONCLUSION: cMet, Cyclin D1, p16 are predictive tumor biomarkers for risk of recurrence and worse disease specific survival in patients with SpSCC