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1.  Model Calibration in the Continual Reassessment Method 
The continual reassessment method (CRM) is an adaptive model-based design used to estimate the maximum tolerated dose in dose finding clinical trials. A way to evaluate the sensitivity of a given CRM model including the functional form of the dose-toxicity curve, the prior distribution on the model parameter, and the initial guesses of toxicity probability at each dose is using indifference intervals. While the indifference interval technique provides a succinct summary of model sensitivity, there are infinitely many possible ways to specify the initial guesses of toxicity probability. In practice, these are generally specified by trial and error through extensive simulations.
By using indifference intervals, the initial guesses used in the CRM can be selected by specifying a range of acceptable toxicity probabilities in addition to the target probability of toxicity. An algorithm is proposed for obtaining the indifference interval that maximizes the average percentage of correct selection across a set of scenarios of true probabilities of toxicity and providing a systematic approach for selecting initial guesses in a much less time consuming manner than the trial and error method. The methods are compared in the context of two real CRM trials.
For both trials, the initial guesses selected by the proposed algorithm had similar operating characteristics as measured by percentage of correct selection, average absolute difference between the true probability of the dose selected and the target probability of toxicity, percentage treated at each dose and overall percentage of toxicity compared to the initial guesses used during the conduct of the trials which were obtained by trial and error through a time consuming calibration process. The average percentage of correct selection for the scenarios considered were 61.5% and 62.0% in the lymphoma trial, and 62.9% and 64.0% in the stroke trial for the trial and error method versus the proposed approach.
We only present detailed results for the empiric dose toxicity curve, although the proposed methods are applicable for other dose toxicity models such as the logistic.
The proposed method provides a fast and systematic approach for selecting initial guesses of probabilities of toxicity used in the CRM that are competitive to those obtained by trial and error through a time consuming process, thus, simplifying the model calibration process for the CRM.
PMCID: PMC2884971  PMID: 19528132
2.  Variability in assessing treatment response: metastatic colorectal cancer as a paradigm 
The cut-off values currently used to categorize tumor response to therapy are neither biologically based nor tailored for measurement reproducibility with contemporary imaging modalities. Sources and magnitudes of discordance in response assessment in metastatic colorectal cancer (mCRC) are unknown.
Experimental Design
A subset of patients’ CT images of chest, abdomen and pelvis were randomly chosen from a multi-center clinical trial evaluating IGF-1R targeted therapy in mCRC. Using Response Evaluation Criteria in Solid Tumors (RECIST), three radiologists selected target lesions and measured UNI (maximal diameter), BI (product of maximal diameter and maximal perpendicular diameter) and VOL (volume) on baseline and 6-week post-therapy scans in the following ways: (1) each radiologist independently selected and measured target lesions and (2) one radiologist’s target lesions were blindly re-measured by the others. Variability in relative change of tumor measurements was analyzed using linear mixed effects models.
Three radiologists independently selected 138, 101 and 146 metastatic target lesions in the liver, lungs, lymph nodes and other organs (e.g., peritoneal cavity) in 29 patients. Of 198 target lesions total, 33% were selected by all three, 28% by two, and 39% by one radiologist. With independent selection, the variability in relative change of tumor measurements was 11% (UNI), 19% (BI) and 22% (VOL), respectively. When measuring the same lesions, the corresponding numbers were 8%, 14% and 12%.
The relatively low variability in change of mCRC measurements suggests that response criteria could be modified to allow more accurate and sensitive CT assessment of anti-cancer therapy efficacy.
PMCID: PMC4337392  PMID: 24780294
RECIST; volume; variability; computed tomography; metastatic colorectal cancer
3.  Calibration of prior variance in the Bayesian Continual Reassessment Method 
Statistics in medicine  2011;30(17):2081-2089.
The continual reassessment method (CRM) is an adaptive model-based design used to estimate the maximum tolerated dose in phase I clinical trials. Asymptotically, the method has been shown to select the correct dose given that certain conditions are satisfied. When sample size is small, specifying a reasonable model is important. While an algorithm has been proposed for the calibration of the initial guesses of the probabilities of toxicity, the calibration of the prior distribution of the parameter for the Bayesian CRM has not been addressed. In this paper, we introduce the concept of least informative prior variance for a normal prior distribution. We also propose two systematic approaches to jointly calibrate the prior variance and the initial guesses of the probability of toxicity at each dose. The proposed calibration approaches are compared with existing approaches in the context of two examples via simulations. The new approaches and the previously proposed methods yield very similar results since the latter used appropriate vague priors. However, the new approaches yield a smaller interval of toxicity probabilities in which a neighboring dose may be selected.
PMCID: PMC3129459  PMID: 21413054
Dose finding; indifference interval; least informative prior; phase I clinical trials
4.  Continual reassessment method with multiple toxicity constraints 
Biostatistics (Oxford, England)  2010;12(2):386-398.
This paper addresses the dose-finding problem in cancer trials in which we are concerned with the gradation of severe toxicities that are considered dose limiting. In order to differentiate the tolerance for different toxicity types and grades, we propose a novel extension of the continual reassessment method that explicitly accounts for multiple toxicity constraints. We apply the proposed methods to redesign a bortezomib trial in lymphoma patients and compare their performance with that of the existing methods. Based on simulations, our proposed methods achieve comparable accuracy in identifying the maximum tolerated dose but have better control of the erroneous allocation and recommendation of an overdose.
PMCID: PMC3062152  PMID: 20876664
Design calibration; Dose-finding cancer trials; Toxicity grades and types
5.  The Citicoline Brain Injury Treatment (COBRIT) Trial: Design and Methods 
Journal of Neurotrauma  2009;26(12):2207-2216.
Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. Despite numerous prior clinical trials no standard pharmacotherapy for the treatment of TBI has been established. Citicoline, a naturally occurring endogenous compound, offers the potential of neuroprotection, neurorecovery, and neurofacilitation to enhance recovery after TBI. Citicoline has a favorable side-effect profile in humans and several meta-analyses suggest a benefit of citicoline treatment in stroke and dementia. COBRIT is a randomized, double-blind, placebo-controlled, multi-center trial of the effects of 90 days of citicoline on functional outcome in patients with complicated mild, moderate, and severe TBI. In all, 1292 patients will be recruited over an estimated 32 months from eight clinical sites with random assignment to citicoline (1000 mg twice a day) or placebo (twice a day), administered enterally or orally. Functional outcomes are assessed at 30, 90, and 180 days after the day of randomization. The primary outcome consists of a set of measures that will be analyzed as a composite measure using a global test procedure at 90 days. The measures comprise the following core battery: the California Verbal Learning Test II; the Controlled Oral Word Association Test; Digit Span; Extended Glasgow Outcome Scale; the Processing Speed Index; Stroop Test part 1 and Stroop Test part 2; and Trail Making Test parts A and B. Secondary outcomes include survival, toxicity, and rate of recovery.
PMCID: PMC2824223  PMID: 19803786
citicoline; clinical trial; COBRIT; therapy; traumatic brain injury
6.  Variability of Spirometry in Chronic Obstructive Pulmonary Disease 
Objective: Our goal is to determine short-term intraindividual biologic and measurement variability in spirometry of patients with a wide range of stable chronic obstructive pulmonary disease severity, using datasets from the National Emphysema Treatment Trial (NETT) and the Lung Health Study (LHS). This may be applied to determine criteria that can be used to assess a clinically meaningful change in spirometry.
Methods: A total of 5,886 participants from the LHS and 1,215 participants from the NETT performed prebronchodilator spirometry during two baseline sessions. We analyzed varying criteria for absolute and percent change of FEV1 and FVC to determine which criterion was met by 90% of the participants.
Results: The mean ± SD FEV1 for the initial session was 2.64 ± 0.60 L (75.1 ± 8.8% predicted) for the LHS and 0.68 ± 0.22 L (23.7 ± 6.5% predicted) for the NETT. The mean ± SD number of days between test sessions was 24.9 ± 17.1 for the LHS and 85.7 ± 21.7 for the NETT. As the degree of obstruction increased, the intersession percent difference of FEV1 increased. However, the absolute difference between tests remained relatively constant despite the severity of obstruction (0.106 ± 0.10 L). Over 90% of participants had an intersession FEV1 difference of less than 225 ml irrespective of the severity of obstruction.
Conclusions: Absolute changes in FEV1 rather than percent change should be used to determine whether patients with chronic obstructive pulmonary disease have improved or worsened between test sessions.
PMCID: PMC2662942  PMID: 16497996
forced expiratory volume; obstructive lung diseases; reproducibility of measurements; spirometry; vital capacity

Results 1-6 (6)