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1.  Bayesian hierarchical modeling of patient subpopulations: Efficient designs of Phase II oncology clinical trials 
Clinical trials (London, England)  2013;10(5):720-734.
Background
In oncology, the treatment paradigm is shifting toward personalized medicine, where the goal is to match patients to the treatments most likely to deliver benefit. Treatment effects in various subpopulations may provide some information about treatment effects in other subpopulations.
Purpose
We compare different approaches to Phase II trial design where a new treatment is being investigated in several groups of patients. We compare considering each group in an independent trial to a single trial with hierarchical modeling of the patient groups.
Methods
We assume four patient groups with different background response rates and simulate operating characteristics of three trial designs, Simon’s Optimal Two-Stage design, a Bayesian adaptive design with frequent interim analyses, and a Bayesian adaptive design with frequent interim analyses and hierarchical modeling across patient groups.
Results
Simon’s designs are based on 10% Type I and Type II error rates. The independent Bayesian designs are tuned to have similar error rates, but may have a slightly smaller mean sample size due to more frequent interim analyses. Under the null, the mean sample size is 2–4 patients smaller. A hierarchical model across patient groups can provide additional power and a further reduction in mean sample size. Under the null, the addition of the hierarchical model decreases the mean sample size an additional 4–7 patients in each group. Under the alternative hypothesis, power is increased to at least 98% in all groups.
Limitations
Hierarchical borrowing can make finding a single group in which the treatment is promising, if there is only one, more difficult. In a scenario where the treatment is uninteresting in all but one group, power for that one group is reduced to 65%. When the drug appears promising in some groups and not in others, there is potential for borrowing to inflate the Type I error rate.
Conclusions
The Bayesian hierarchical design is more likely to correctly conclude efficacy or futility than the other two designs in many scenarios. The Bayesian hierarchical design is a strong design for addressing possibly differential effects in different groups.
doi:10.1177/1740774513497539
PMCID: PMC4319656  PMID: 23983156
2.  Bayesian approaches for comparative effectiveness research 
Background
A hallmark of comparative effectiveness research is the analysis of all the available evidence from different studies addressing a given question of medical risk versus benefit. The Bayesian statistical approach is ideally suited for such investigations because it is inherently synthetic and because it is philosophically uninhibited regarding the ability to analyze all the available evidence.
Purpose
To consider a variety of comparative effectiveness research settings and show how the Bayesian approach applies.
Methods
The Bayesian approach is described as it has been applied to the comparative analysis of implantable cardioverter defibrillators and mammographic screening, in the Cancer Intervention and Surveillance Modeling Network, in comparisons of patient outcomes data from different sources, and in designing adaptive clinical trials to support the development of ‘personalized medicine.’
Results
Bayesian methods allow for continued learning as data accrue and for cumulating meta-analyses and the comparison of heterogeneous studies. Bayesian methods enable predictive probability distributions of the results of future studies.
Limitations
Bayesian posterior distributions are subject to potential bias – in the selection of ‘available’ evidence and in the choice of a likelihood model. Sensitivity analyses help to control this bias.
Conclusions
The Bayesian approach has much to offer comparative effectiveness research. It provides a mechanism for synthesizing various sources of information and for updating knowledge in an online fashion as evidence accumulates.
doi:10.1177/1740774511417470
PMCID: PMC4314707  PMID: 21878446
3.  [No title available] 
PMCID: PMC3935382  PMID: 24311736
4.  [No title available] 
PMCID: PMC3946398  PMID: 24216219
5.  [No title available] 
PMCID: PMC3946437  PMID: 24082004
6.  Use of Health Plan Combined with Registry Data to Predict Clinical Trial Recruitment 
Background
Large pragmatic clinical trials (PCTs) are increasingly used to conduct comparative effectiveness research. In the context of planning a safety PCT of the live herpes zoster vaccine in rheumatoid arthritis (RA) patients age ≥ 50 receiving anti- tumor necrosis factor (TNF) therapy, we evaluated the use of health plan combined with registry data to assess the feasibility of recruiting the 4,000 patients needed for the trial and to facilitate site selection.
Methods
Using national United States data from Medicare, we identified older RA patients who received anti-TNF therapy in the last quarter of 2009. Extrapolations were made from the Medicare patient population to younger patients and those with other types of insurance using the Consortium of Rheumatology Researchers of North America (CORRONA) disease registry. Patients’ treating rheumatologists were grouped into practices and sorted by size from the greatest to the least number of eligible patients.
Results
Approximately 50,000 RA patients receiving anti-TNF therapy were identified in the Medicare data, distributed across 1,980 physician practices. After augmenting Medicare data with information from CORRONA and extrapolating to younger patients and those with other types of insurance, more than 12,000 potentially eligible study subjects were identified from the 40-45 largest rheumatology practices.
Conclusion
Health plan and registry databases appear useful to assess feasibility of large pragmatic trials and to assist in selection of recruitment sites with the greatest number of potentially eligible patients. This novel approach is applicable to trials with simple inclusion/exclusion criteria that can be readily assessed in these data sources.
doi:10.1177/1740774513512185
PMCID: PMC4199104  PMID: 24346611
pragmatic trial; clinical trial; registry; administrative data; recruitment; rheumatoid arthritis; anti-TNF therapy; herpes zoster; shingles
7.  SEARS: A Seamless Dose Escalation/Expansion with Adaptive Randomization Scheme 
Background
Standard drug development conducts phase I dose finding and phase II dose expansion sequentially and separately. Information between the two phases is rarely shared. Administratively, such a sequential process is time consuming and burdensome.
Purpose
We propose SEARS, a seamless design that combines phase I dose escalation based on toxicity with phase II dose expansion and dose comparison based on efficacy. SEARS allows extension from phase I to phase II under one design with no gap in between, and employs a dynamic and parallel procedure involving simultaneous dose escalation, dose graduation, and adaptive randomization.
Methods
SEARS integrates three components into a seamless scheme. Specifically, in phase I, SEARS applies the mTPI method to monitor dose escalation based on toxicity outcome. Doses that show promising efficacy and safety are immediately graduated from phase I and placed to a phase II stage in which patients are adaptively randomized based on efficacy outcome. Phase I dose escalation, dose graduation, and phase II adaptive randomization proceed simultaneously throughout the entire trial.
Results
Examples are given comparing SEARS with two other designs, in which superior performance of SEARS is demonstrated. An important and promising finding is that SEARS reduces sample sizes without losing power. R program and demo slides of SEARS can be obtained at http://www.northshore.org/research/investigators/yuan-ji-phd/
Limitation
We assume that the binary efficacy and toxicity response can be measured in the same time frame. This is often achievable with surrogate efficacy markers in practice.
doi:10.1177/1740774513500081
PMCID: PMC4281526  PMID: 24137041
Bayesian adaptive designs; Graduation rule; Phase I; Phase II; Seamless
8.  Hormonal regulators of muscle and metabolism in aging (HORMA): design and conduct of a complex, double masked multicenter trial 
Background
Older persons often lose muscle mass, strength, and physical function. This report describes the challenges of conducting a complex clinical investigation assessing the effects of anabolic hormones on body composition, physical function, and metabolism during aging.
Methods
HORMA is a multicenter, randomized double masked study of 65–90-year-old community dwelling men with testosterone levels of 150–550 ng/dL and IGF-1 < 167 ng/dL. Subjects were randomized to transdermal testosterone (5 or 10 g/day) and rhGH (0, 3, or 5 μg/kg/day) for 16 weeks. Outcome measures included body composition by DEXA, MRI, and 2H2O dilution; muscle performance (strength, power, and fatigability), VO2peak, measures of physical function, synthesis/breakdown of myofibrillar proteins, other measures of metabolism, and quality of life.
Results
Major challenges included delay in startup caused by need for 7 institutional contracts, creating a 142-page manual of operations, orientation and training, creating a 121-page CRF; enrollment inefficiencies; scheduling 16 evaluations/subject; overnight admissions for invasive procedures and isotope infusions; large data and image management and transfer; quality control at multiples sites; staff turnover; and replacement of a clinical testing site. Impediments were largely solved by implementation of a web-based data entry and eligibility verification; electronic scheduling for multiple study visits; availability of research team members to educate and reassure subjects; more frequent site visits to validate all source documents and reliability of data entry; and intensifying quality control in testing and imaging. The study exceeded the target goal of 108 (n =112) completely evaluable cases. Two interim DSMB meetings confirmed the lack of excessive adverse events, lack of center effects, comparability of subjects, and that distribution of subjects and enrollment will not jeopardize outcomes or generalizability of results.
Conclusions
Flexibility and rapidly solving evolving problems is critical when conducting highly complex multicenter metabolic studies.
doi:10.1177/1740774507083569
PMCID: PMC4301418  PMID: 17942471
9.  Comparison of dynamic block randomization and minimization in randomized trials: a simulation study 
Background
Minimizing the imbalance of key baseline covariates between treatments is known to be very important to the precision of the estimate of treatment effect in clinical research. Dynamic randomization allocation techniques have been used to achieve balance across multiple baseline characteristics. However, empirical data are limited on how these techniques compare in terms of balance and efficiency. We are motivated by a newly funded randomized controlled trial, in which we have the option of choosing between two methods of randomization at the subject level: (1) randomizing individual subjects consecutively as they are enrolled, using Pocock and Simon’s minimization method, and (2) simultaneously randomizing blocks of subjects once all subjects in a block have been enrolled, using a balance algorithm originally developed for cluster randomized trials.
Purpose
To compare dynamic block randomization and minimization in terms of balance on baseline covariates and statistical efficiency. Simple randomization was included as a reference.
Methods
A simulation study using data from a previous randomized controlled trial was conducted to compare balance statistics and the accuracy and power of hypothesis testing among the randomization methods.
Results
Dynamic block randomization consistently produced the best balance and highest power for various sample and treatment effect sizes, even after post-adjustment of the pre-specified baseline covariates in all three methods. Consistent with previous reports, minimization performed better in balance and power than simple randomization; however, the differences were noticeably smaller compared to those between dynamic block randomization and simple randomization.
Limitations
In this simulation study, we considered three sample sizes and two block sizes for a two-arm randomized trial. We assumed no interactions among the multiple baseline covariates. It is necessary to evaluate how the results may vary when the simulation conditions are changed before drawing broader conclusions regarding comparisons between the randomization methods.
Conclusions
This study demonstrates that dynamic block randomization outperforms minimization with regard to achieving balance and maximizing efficiency. Nevertheless, the differences across the three randomization strategies are modest. The statistical advantages associated with dynamic block randomization need to be considered in relation to the planned sample size and the practical issues for its implementation in deciding the preferred method of randomization for a given trial (e.g., the time required to accrue blocks of subjects of adequate size as balanced against the need to commence intervention/treatment immediately in those randomized to that experimental condition).
doi:10.1177/1740774510391683
PMCID: PMC4296975  PMID: 21335590
10.  Clinical trial designs for testing biomarker-based personalized therapies 
Background
Advances in molecular therapeutics in the past decade have opened up new possibilities for treating cancer patients with personalized therapies, using biomarkers to determine which treatments are most likely to benefit them, but there are difficulties and unresolved issues in the development and validation of biomarker-based personalized therapies. We develop a new clinical trial design to address some of these issues. The goal is to capture the strengths of the frequentist and Bayesian approaches to address this problem in the recent literature and to circumvent their limitations.
Methods
We use generalized likelihood ratio tests of the intersection null and enriched strategy null hypotheses to derive a novel clinical trial design for the problem of advancing promising biomarker-guided strategies toward eventual validation. We also investigate the usefulness of adaptive randomization (AR) and futility stopping proposed in the recent literature.
Results
Simulation studies demonstrate the advantages of testing both the narrowly focused enriched strategy null hypothesis related to validating a proposed strategy and the intersection null hypothesis that can accommodate to a potentially successful strategy. AR and early termination of ineffective treatments offer increased probability of receiving the preferred treatment and better response rates for patients in the trial, at the expense of more complicated inference under small-to-moderate total sample sizes and some reduction in power.
Limitations
The binary response used in the development phase may not be a reliable indicator of treatment benefit on long-term clinical outcomes. In the proposed design, the biomarker-guided strategy (BGS) is not compared to ‘standard of care’, such as physician’s choice that may be informed by patient characteristics. Therefore, a positive result does not imply superiority of the BGS to ‘standard of care’. The proposed design and tests are valid asymptotically. Simulations are used to examine small-to-moderate sample properties.
Conclusion
Innovative clinical trial designs are needed to address the difficulties and issues in the development and validation of biomarker-based personalized therapies. The article shows the advantages of using likelihood inference and interim analysis to meet the challenges in the sample size needed and in the constantly evolving biomarker landscape and genomic and proteomic technologies.
doi:10.1177/1740774512437252
PMCID: PMC4296980  PMID: 22397801
11.  The Children’s Attention-deficit Hyperactivity Disorder (ADHD) Telemental Health Treatment Study: Methodology for Conducting a Trial of Telemental Health in Multiple Underserved Communities 
Clinical trials (London, England)  2013;10(6):949-958.
Background
Children who live in non-metropolitan communities are underserved by evidence-based mental health care and underrepresented in clinical trials of mental health services. Telemental Health (TMH), the use of videoteleconferencing (VTC) to provide care that is usually delivered in person, shows promise for helping to rectify these service disparities.
Purpose
The Children’s ADHD Telemental Health Treatment Study (CATTS) is a randomized controlled trial designed to test the effectiveness of TMH in providing treatment to children diagnosed with attention-deficit hyperactivity disorder (ADHD) who are living in underserved communities. In this paper we describe the methodologies we developed for the trial and lessons learned.
Methods
Children ages 5.5-12 years of age with ADHD were referred to CATTS by their primary care physicians (PCP’s). The test intervention group (Group A) received six telepsychiatry sessions followed by in-person caregiver behavioral training delivered by a local therapist who was trained and supervised remotely. A secure website was used to support decision-making by the telepsychiatrists, to facilitate real-time collaboration between the telepsychiatrists and community therapists, and communication with the PCP’s. The control group (Group B) received a single telepsychiatry consultation followed by treatment with their PCP’s who implemented the telepsychiatrists’ recommendations at their discretion.
Caregivers completed five sets of questionnaires about children’s symptoms and functioning and their own levels of distress. Older children (aged 10-12 years) completed questionnaires about their symptoms and functioning. Teachers completed ADHD rating scales. Questionnaires were completed online through a secure portal from personal computers.
Results
Eighty-eight PCP’s in seven communities referred the 223 children who participated in the trial. Attrition was low (3%). Children in Group A completed an average of 5.3 of 6 scheduled sessions; 96% of children in Group B completed their telepsychiatry consultation. Parents in both groups completed an average of 4.8 of 5 assessments. Telepsychiatrists and therapists showed high adherence to treatment protocols.
Lessons Learned
TMH proved to be a viable means of providing evidence-based pharmacological services to children and of training local therapists in evidence-based caregiver behavioral management. Recruitment was enhanced by offering the control group a telepsychiatry consultation. To meet recruitment targets across multiple dispersed sites, we developed community-specific strategies. A dedicated scheduler was a critical staff role to coordinate the multiple sites, sessions, and clinicians. Trial implementation was easier with sites that shared an electronic medical record system with our research hub.
Conclusions
The CATTS study used methods and procedures to optimize inclusion of children living in multiple dispersed and underserved areas. These experiences should advance the development of technologies needed to recruit underserved populations into research projects with the goal of reducing disparities in access to quality mental health care.
doi:10.1177/1740774513494880
PMCID: PMC4286399  PMID: 23897950
Telemental health; Telepsychiatry; Videoteleconferencing; Children’s mental health; Mental health disparities; Telecommunications
12.  A Bayesian approach for unplanned sample sizes in phase II cancer clinical trials 
Background
Phase II cancer clinical trials commonly employ two-stage designs that incorporate a single interim analysis for lack of efficacy and are designed to achieve specified frequentist properties. The requirement to examine the outcome at a prespecified sample size (SS) can be problematic, because the attained SS often differs from the planned SS.
Purpose
We propose to address unplanned SSs achieved at either stage by means of a Bayesian approach that approximately preserves the original design’s properties.
Methods
Our approach translates the rejection rule of the original frequentist design into equivalent statements about the posterior distribution of the response rate and applies this Bayesian criterion to the analysis with any realized SS.
Results
The results demonstrate that our approach approximately maintains operating characteristics of the original frequentist design including type I and type II error rates, probability of early termination, and expected SS under the null hypothesis.
Limitations
Designs attained under this approach may not satisfy target limits for type I error rate and power.
Conclusions
Our method offers a coherent analysis plan when the attained SS at either stage deviates from that specified in the original design. The price of its flexibility, in terms of erosion of the desired frequentist properties, is modest.
doi:10.1177/1740774512443429
PMCID: PMC4283461  PMID: 22523304
13.  The Superiority of the Time-to-Event Continual Reassessment Method to the Rolling Six Design in Pediatric Oncology Phase I Trials 
Background
The Rolling Six Design (RSD) is currently being used by the Children’s Oncology Group (COG) as their standard design for Phase I trials. Because the COG has large multi-center trials with fast accrual, the motivation for adopting the RSD is to hasten accrual and shorten the duration of their trials. However, trial suspension due to completion of follow-up still cannot be entirely avoided by the RSD. Therefore, a design that allows continuous enrollment of patients throughout the entire trial is needed.
Purpose
To demonstrate the superior performance of the Time-to-Event Continual Reassessment Method (TITE-CRM) with continuous patient recruitment relative to the RSD, in terms of identifying the maximum tolerated dose (MTD) and reducing exposure of patients to toxic doses.
Methods
Using scenarios that were based on an actual pediatric Phase I trial at the University of Michigan, Monte Carlo simulations were used to investigate the operational characteristics of RSD and TITE-CRM.
Results
The TITE-CRM treated all available patients, identified the MTD more accurately than the RSD and did not increase the probability of exposing patients to toxic doses.
Limitations
Both the TITE-CRM and RSD assume that the probability of dose limiting toxicity increases with higher dose level.
Conclusions
The TITE-CRM, which allows for continual enrollment of patients, provides a safe design for pediatric oncology Phase I trials with better accuracy than the RSD.
doi:10.1177/1740774511407533
PMCID: PMC4281887  PMID: 21610004
14.  Recruiting and retaining pregnant women from a community health center at the US–Mexico border for the Mothers and Youth Access clinical trial 
Background
Recruitment and retention in clinical trials of minorities is low, particularly in rural underserved populations. This has slowed progress in addressing racial/ethnic disparities in oral health.
Purpose
To describe factors associated with successful recruitment, and identify predictors of continued retention of pregnant women attending a community health center into a randomized controlled clinical trial to prevent early childhood caries.
Methods
The Mothers and Youth Access (MAYA) Trial recruited women in the second trimester of pregnancy. At baseline, consenting women completed an oral health questionnaire and received a dental exam and oral health counseling. Four months postpartum, women returned with their babies for randomization with follow up at 9-, 12-, 18-, 24-, 30-, and 36-month postpartum visits. To assess predictors of retention, data about respondents’ demographics, and oral health-related knowledge, attitudes, and behaviors were obtained by questionnaire and analyzed by logistic and discrete time-to-event regression analyses.
Results
Of 556 predominantly Mexican-American women recruited at baseline, 195 (35%) were excluded after baseline for not meeting inclusion criteria; 361 (65%) continued to randomization. Factors such as race/ethnicity, annual household income, household composition, oral health-related knowledge and behaviors significantly related to retention until randomization. In multivariable models, women reporting a higher annual household income were less likely to be lost to attrition before randomization (odds ratio = 0.73, 95% confidence interval (CI) 0.60–0.89); while Mexican/Mexican-American women were less likely to be lost beyond randomization (hazard ratio = 0.53, 95% CI 0.26–1.08).
Limitations
Factors not measured at baseline may have been important in predicting attrition. The MAYA Trial is expected to finish by November 2008; therefore, complete results for total retention may differ from those reported here.
Conclusions
Recruitment and retention efforts for pregnant Hispanic women should place heavy emphasis on culture as ethnicity remained the only borderline significant predictor in post randomization retention.
doi:10.1177/1740774508093980
PMCID: PMC4238942  PMID: 18697848
15.  Multicenter trials using FDG PET to predict chemotherapy response : Effects of differential measurement error and bias on power calculations for unselected and enrichment designs 
Clinical trials (London, England)  2013;10(6):886-895.
doi:10.1177/1740774513506618
PMCID: PMC4103752  PMID: 24169628
predictive biomarker; FDG PET imaging; multicenter; measurement error; bias; power; design
16.  Motivations of patients with pulmonary arterial hypertension to participate in randomized clinical trials 
Background
There is substantial need to rigorously evaluate existing and new therapies for pulmonary arterial hypertension (PAH) and other severe and relatively rare conditions affecting younger patients. However, the ability to conduct meaningful randomized clinical trials (RCTs) in such contexts often is limited by difficulties obtaining adequate patient enrollment.
Purpose
To understand the motivations of patients with PAH for participating in RCTs so as to facilitate enrollment in future trials among patients with similar diseases.
Methods
We conducted semistructured interviews of a diverse sample of patients with World Health Organization (WHO) Group I PAH. We purposefully recruited a diverse sample of participants until theoretical saturation was reached. We randomly assigned patients to review hypothetical RCTs that did or did not allow continuation of background PAH therapies and elicited their reasons for or against enrolling. Interviews were transcribed and analyzed using constant comparison techniques to code and sort data into discrete themes.
Results
The 26 PAH patients enrolled before theoretical saturation was reached identified 24 factors that would influence their RCT enrollment decisions. These factors grouped naturally into four themes: (1) personal medical benefits, (2) personal medical risks/harms, (3) nonmedical benefits, and (4) nonmedical burdens. Personal benefits were cited as commonly as altruistic motives. One third of the patients (9/26) suggested that they would defer enrollment decisions to their treating clinicians. Seventy-nine percent of patients (11/14) assigned to consider trials without background therapies expressed concerns about clinical deterioration (vs. 17% (2/12) among patients assigned to consider trials allowing background therapies).
Limitations
The sample was recruited from a single academic center. Furthermore, the use of hypothetical trials may not elicit identical decision-making processes as may be used among patients contemplating actual trial participation.
Conclusion
For PAH patients considering RCT enrollment, the potentials for personal benefit and risk are at least as important as altruistic motives. Minimizing the time demands of participating, financial remuneration, and allowing participants to continue current therapies are factors, which might enhance enrollment to trials in similar disease areas.
doi:10.1177/1740774512438981
PMCID: PMC4212936  PMID: 22388077
17.  Managing clinical research permissions electronically 
Clinical trials (London, England)  2013;10(4):604-611.
Background
One mechanism to increase participation in research is to solicit potential research participants’ general willingness to be recruited into clinical trials. Such research permissions and consents typically are collected on paper upon patient registration. We describe a novel method of capturing this information electronically.
Purpose
The objective is to enable the collection of research permissions and informed consent data electronically to permit tracking of potential research participants’ interest in current and future research involvement and to provide a foundation for facilitating the research workflow.
Methods
The project involved systematic analysis focused on key areas, including existing business practices, registration processes, and permission collection workflows, and ascertaining best practices for presenting consent information to users via tablet technology and capturing permissions data. Analysis was followed by an iterative software development cycle with feedback from subject matter experts and users.
Results
An initial version of the software was piloted at one institution in South Carolina for a period of 1 year, during which consents and permission were collected during 2524 registrations of patients. The captured research permission data were transmitted to a clinical data warehouse. The software was later released as an open-source package that can be adopted for use by other institutions.
Limitations
There are significant ethical, legal, and informatics challenges that must be addressed at an institution to deploy such a system. We have not yet assessed the long-term impact of the system on recruitment of patients to clinical trials.
Conclusions
We propose that by improving the ability to track willing potential research participants, we can improve recruitment into clinical trials and, in the process, improve patient education by introducing multimedia to informed consent documents.
doi:10.1177/1740774513491338
PMCID: PMC4213063  PMID: 23785065
18.  Reconnecting with urban youth enrolled in a randomized controlled trial and overdue for a 12-month follow-up survey 
Clinical trials (London, England)  2013;10(5):775-782.
Background
Retention of study participants in randomized controlled trials (RCTs) is crucial to study validity.
Purpose
We analyzed the result of four retention strategies used to reconnect with urban teens enrolled in a school-based randomized controlled trial (RCT) and overdue for a 12-month follow-up survey.
Methods
Traditional retention strategies used to reconnect with teens categorized as “unable to contact” were weekly re-dials of non-working telephone numbers and mailings to the student’s home. Non-traditional retention strategies were obtaining assistance from school administration and communication through Facebook.
Results
Of the 422 students enrolled, 125 (29.5%) were overdue for a 12-month follow-up survey, but had no working telephone number (unable to contact). We made 196 attempts to contact these 125 students, of which 82 attempts (41.8%) were successful in “reconnecting,” defined as (1) a student contacting research staff as a result of a mailed notice; (2) a research staff member leaving a voicemail at a previously disconnected telephone number; (3) a student responding to Facebook outreach; or (4) research staff obtaining a new telephone number and talking to a person at the new telephone number. We used “ mailed reminder letters” as the referent category, in our analysis. Odds ratios (95% confidence intervals) for the association between the strategy used and success (“reconnecting”) for telephone number re-dials, Facebook, and school administration assistance were 4.60 (1.8–11.8), 1.94 (1.01–3.73), and 2.91 (0.58–14.50), respectively.
Limitations
Retention strategies were not applied hierarchically or systematically across students, and we were unable to ascertain student preference for a particular strategy. In addition, our findings may be applicable only to study populations with characteristics similar to those of students included in this study.
Conclusion
Overall, of the 422 students who enrolled in the study, 380 (90%), ultimately completed the 12-month follow-up survey. A mix of traditional retention strategies, such as telephone number re-dials, and more contemporary methods, such as use of Facebook, were effective in reconnecting with urban teenagers enrolled in a school-based RCT, and controlling attrition during the 12-month follow-up survey period.
doi:10.1177/1740774513498320
PMCID: PMC3800210  PMID: 23983157
Retention; adherence; attrition; urban teens; students; asthma management; intervention; randomized controlled trial; Facebook; social networking
19.  Imperfect Gold Standards for Biomarker Evaluation 
Clinical trials (London, England)  2013;10(5):696-700.
Background
Serum creatinine has been used as the diagnostic test for acute kidney injury (AKI) for decades despite having imperfect sensitivity and specificity. Novel tubular injury biomarkers may revolutionize the diagnosis of acute kidney injury; however, even if a novel tubular injury biomarker is 100% sensitive and 100% specific, it may appear inaccurate when using serum creatinine as the gold standard.
Conclusions
In general, the apparent diagnostic performance of a biomarker depends not only on its ability to detect injury but also on disease prevalence and the sensitivity and specificity of the imperfect gold standard. Apparent errors in diagnosis using a new biomarker may be a reflection of errors in the imperfect gold standard itself rather than poor performance of the biomarker.
doi:10.1177/1740774513497540
PMCID: PMC3800226  PMID: 24006246
20.  Assessment of Biomarkers for Risk Prediction with Nested Case Control Studies 
Clinical trials (London, England)  2013;10(5):677-679.
Accurate risk prediction plays a key role in disease prevention and disease management; emergence of new biomarkers may lead to an important question about how much improvement in prediction accuracy it would achieve by adding the new markers into the existing risk prediction tools. However, in large prospective cohort studies, the standard full-cohort design, requiring marker measurement on the entire cohort, may be infeasible due to cost and low rate of the clinical condition of interest. To overcome such difficulties, nested case-control (NCC) studies provide cost-effective alternatives but bring about challenges in statistical analyses due to complex datasets generated. To evaluate prognostic accuracy of a risk model, Cai and Zheng1 proposed a class of nonparametric inverse probability weighting (IPW) estimators for accuracy measures in the time-dependent receiver operating characteristic curve analysis. To accommodate a three-phase NCC design in Nurses' Health Study, we extend the double IPW estimators of Cai and Zheng1 to develop risk prediction models under time-dependent generalized linear models and evaluate the incremental values of new biomarkers and genetic markers. Our results suggest that aggregating the information from both the genetic markers and biomarkers substantially improves the accuracy for predicting 5-year and 10-year risks of rheumatoid arthritis.
doi:10.1177/1740774513498321
PMCID: PMC3800233  PMID: 24013405
21.  The National Drug Abuse Treatment Clinical Trials Network Data Share Project: Website Design, Usage, Challenges and Future Directions 
Clinical trials (London, England)  2013;10(6):977-986.
Background
The are many benefits of data sharing, including the promotion of new research from effective use of existing data, replication of findings through re-analysis of pooled data files, meta-analysis using individual patient data, and reinforcement of open scientific inquiry. A randomized controlled trial is considered as the “gold standard” for establishing treatment effectiveness, but clinical trial research is very costly and sharing data is an opportunity to expand the investment of the clinical trial beyond its original goals at minimal costs.
Purpose
We describe the goals, developments, and usage of the Data Share website (www.ctndatashare.org) for the National Drug Abuse Treatment Clinical Trials Network (CTN) in the US, including lessons learned, limitations and major revisions and considerations for future directions to improve data sharing.
Methods
Data management and programming procedures were conducted to produce uniform and Health Insurance Portability and Accountability Act (HIPAA)-compliant de-identified research data files from the completed trials of the CTN for archiving, managing, and sharing on the Data Share website.
Results
Since its inception in 2006 and through October 2012, nearly 1700 downloads from 27 clinical trials have been accessed from the Data Share website, with the use increasing over the years. Individuals from 31 countries have downloaded data from the website, and there have been at least 13 publications derived from analyzing data through the public Data Share website.
Limitations
Minimal control over data requests and usage has resulted in little information and lack of control regarding how the data from the website are used. Lack of uniformity in data elements collected across CTN trials has limited cross-study analyses.
Conclusions
The Data Share website offers researchers easy access to deidentified data files with the goal to promote additional research and identify new findings from completed CTN studies. To maximize the utility of the website, on-going collaborative efforts are needed to standardize the core measures used for data collection in the CTN studies with the goal to increase their comparability and to facilitate the ability to pool data files for cross-study analyses.
doi:10.1177/1740774513503522
PMCID: PMC3994893  PMID: 24085772
24.  Usefulness of prestudy assessment of patient willingness to undergo tissue biopsy for correlative studies in a melanoma vaccine trial 
Clinical trials (London, England)  2012;10(1):143-150.
Background
Performing biopsies for correlative studies in cancer trials raises ethical and regulatory concerns and may impact trial accrual negatively. However, strategies to address these concerns remain largely unexplored.
Purpose
We sought to assess the perceived risk of mandatory tissue biopsies to be performed for research purposes as part of a clinical trial of a melanoma vaccine by administering a pretrial accrual assessment questionnaire in the population of interest. Furthermore, we explored how such survey data may be used to address potential concerns of regulatory and funding organizations that may not be able to assess the risks of those biopsies.
Method
A total of 91 melanoma patients, similar to potential participants in a melanoma vaccine pilot study, scored their willingness, on a 9-point Likert scale, to participate in vaccine trials involving no skin biopsy versus a skin biopsy resulting in a 3-, 6-, or 12-cm scar. The vaccine trial was performed with skin biopsies leaving a 6-cm scar. Accrual rate was assessed and that accrual was compared to the accrual of two similar vaccine trials without biopsy requirements.
Results
A total of 95% of the participants expressed willingness to enter a vaccine trial (likely to highly likely). This proportion decreased to 74%, 63%, and 59%, respectively, for vaccine trials requiring skin biopsy leaving a 3-, 6-, or 12-cm scar. The trial was designed with an estimated 40% decrease in accrual rate compared to prior studies (2 participants expected/month). The resulting trial with a 6-cm biopsy exceeded that accrual rate estimate and had a similar accrual rate to vaccine trials without a biopsy (4.1 vs 2.7–4.6 participants/month).
Limitations
Potential limitations of this study include the exclusion of some questionnaire responses and the post hoc nature of the analysis.
Conclusion
Willingness to participate in vaccine trials was decreased by the requirement for skin biopsy, but the size of the biopsy was less of a deterrent than expected. Findings from brief surveys may aid in risk assessment during regulatory review, predict acceptability of tissue collection for correlative studies, and support regulatory approval and meeting accrual goals of the study.
doi:10.1177/1740774512464438
PMCID: PMC4167396  PMID: 23197414
25.  Sample size formulae for the Bayesian continual reassessment method 
Clinical trials (London, England)  2013;10(6):10.1177/1740774513497294.
Background
In the planning of a dose finding study, a primary design objective is to maintain high accuracy in terms of the probability of selecting the maximum tolerated dose. While numerous dose finding methods have been proposed in the literature, concrete guidance on sample size determination is lacking.
Purpose
With a motivation to provide quick and easy calculations during trial planning, we present closed form formulae for sample size determination associated with the use of the Bayesian continual reassessment method.
Methods
We examine the sampling distribution of a nonparametric optimal design, and exploit it as a proxy to empirically derive an accuracy index of the continual reassessment method using linear regression.
Results
We apply the formulae to determine the sample size of a phase I trial of PTEN-long in pancreatic patients, and demonstrate that the formulae give very similar results to simulation. The formulae are implemented by an R function ‘getn’ in the package ‘dfcrm’.
Limitations
The results are developed for the Bayesian continual reassessment method, and should be validated by simulation when used for other dose finding methods.
Conclusions
The analytical formulae we propose give quick and accurate approximation of the required sample size for the continual reassessment method. The approach used to derive the formulae can be applied to obtain sample size formulae for other dose finding methods.
doi:10.1177/1740774513497294
PMCID: PMC3843987  PMID: 23965547

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