Design considerations for two-stage enrichment clinical trials.

When there is a predictive biomarker, enrichment can focus the clinical trial on a benefiting subpopulation. We describe a two-stage enrichment design, in which the first stage is designed to efficiently estimate a threshold and the second stage is a "phase III-like" trial on the enriched population. The goal of this paper is to explore design issues: sample size in Stages 1 and 2, and re-estimation of the Stage 2 sample size following Stage 1.

Understanding Research Methods: Up-and-down Designs for Dose-finding.

For the task of estimating a target benchmark dose such as the ED50 (the dose that would be effective for half the population), an adaptive dose-finding design is more effective than the standard approach of treating equal numbers of patients at a set of equally spaced doses. Up-and-down is the most popular family of dose-finding designs and is in common use in anesthesiology. Despite its widespread use, many aspects of up-and-down are not well known, implementation is often misguided, and standard, up-to-date reference material about the design is very limited.

Distribution Theory Following Blinded and Unblinded Sample Size Re-estimation under Parametric Models.

Asymptotic distribution theory for maximum likelihood estimators under fixed alternative hypotheses is reported in the literature even though the power of any realistic test converges to one under fixed alternatives. Under fixed alternatives, authors have established that nuisance parameter estimates are inconsistent when sample size re-estimation (SSR) follows blinded randomization. These results have helped to inhibit the use of SSR.

Most Powerful Test Sequences with Early Stopping Options.

We extended the application of uniformly most powerful tests to sequential tests with different stage-specific sample sizes and critical regions. In the one parameter exponential family, likelihood ratio sequential tests are shown to be uniformly most powerful for any predetermined -spending function and stage-specific sample sizes. To obtain this result, the probability measure of a group sequential design is constructed with support for all possible outcome events, as is useful for designing an experiment prior to having data.

Discussion on "Adaptive enrichment designs with a continuous biomarker" by Nigel Stallard.

We congratulate Dr. Nigel Stallard on his stimulating paper on adaptive enrichment designs with a continuous biomarker. Dr.

Choosing Interim Sample Sizes in Group Sequential Designs.

This manuscript investigates sample sizes for interim analyses in group sequential designs. Traditional group sequential designs (GSD) rely on "information fraction" arguments to define the interim sample sizes. Then, interim maximum likelihood estimators (MLEs) are used to decide whether to stop early or continue the data collection until the next interim analysis.

Asymptotic properties of maximum likelihood estimators with sample size recalculation.

Consider an experiment in which the primary objective is to determine the significance of a treatment effect at a predetermined type I error and statistical power. Assume that the sample size required to maintain these type I error and power will be re-estimated at an interim analysis. A secondary objective is to estimate the treatment effect.

Bias induced by adaptive dose-finding designs.

There is a long literature on bias in maximum likelihood estimators. Here we demonstrate that adaptive dose-finding procedures (such as Continual Reassessment Methods, Up-and-Down and Interval Designs) themselves induce bias. In particular, with Bernoulli responses and dose assignments that depend on prior responses, we provide an explicit formula for the bias of observed response rates.

Salt marsh denitrification is impacted by oiling intensity six years after the Deepwater Horizon oil spill.

Coastal salt marshes provide the valuable ecosystem service of removing anthropogenic nitrogen (N) via microbially-mediated denitrification. During the 2010 Deepwater Horizon (DWH) spill, oil exposure killed marsh plants in some regions and contributed to rapid compositional shifts in sediment microbial communities, which can impact ecosystem denitrification capacity. Within 3-5 years of the spill, plant biomass and microbial communities in some impacted marshes can recover to a new stable state.

Vegetation Loss Decreases Salt Marsh Denitrification Capacity: Implications for Marsh Erosion.

Salt marshes play a key role in removing excess anthropogenic nitrogen (N) loads to nearshore marine ecosystems through sediment microbial processes such as denitrification. However, in the Gulf of Mexico, the loss of marsh vegetation because of human-driven disturbances such as sea level rise and oil spills can potentially reduce marsh capacity for N removal. To investigate the effect of vegetation loss on ecosystem N removal, we contrasted denitrification capacity in marsh and subtidal sediments impacted by the Deepwater Horizon oil spill using a combination of N and N production (isotope pairing), denitrification potential measurements (acetylene block), and quantitative polymerase chain reaction (qPCR) of functional genes in the denitrification pathway.

Comparison of Isotonic Designs for Dose-Finding.

We compare several decision rules for allocating subjects to dosages that are based on sequential isotonic estimates of a monotone dose-toxicity curve. We conclude that the decision rule in which the next assignment is to the dose having probability of toxicity closest to target does not work well. The best rule in our comparison is given by the cumulative cohort design.

Development and validation of a measure of dysmorphology: useful for autism subgroup classification.

Autism spectrum disorders (ASD) comprise a class of neurodevelopmental disorders that can originate from a variety of genetic and environmental causes. To delineate autism's heterogeneity we have looked for biologically-based phenotypes found in consistent proportions of ASD individuals. One informative phenotype is that of generalized dysmorphology, based on whole body examinations by medical geneticists trained in the nuances of anomalous embryologic development.

Quantile estimation following non-parametric phase I clinical trials with ordinal response.

A non-parametric multi-dimensional isotonic regression estimator is developed for use in estimating a set of target quantiles from an ordinal toxicity scale. We compare this estimator to the standard parametric maximum likelihood estimator from a proportional odds model for extremely small data sets. A motivating example is from phase I oncology clinical trials, where various non-parametric designs have been proposed that lead to very small data sets, often with ordinal toxicity response data.

Estimating the probability of toxicity at the target dose following an up-and-down design.

One of the most important aspects of a phase I trial or other acute toxicity study is estimating accurately the probability of toxicity that is associated with the recommended dose. We use the biased coin up-and-down design to allocate and isotonic regression to estimate toxicity probabilities and determine the recommended dose. We then derive, using bootstrap methods, an estimate of the probability of toxicity at the recommended dose.

Dose finding using the biased coin up-and-down design and isotonic regression.

We are interested in finding a dose that has a prespecified toxicity rate in the target population. In this article, we investigate five estimators of the target dose to be used with the up-and-down biased coin design (BCD) introduced by Durham and Flournoy (1994, Statistical Decision Theory and Related Topics). These estimators are derived using maximum likelihood, weighted least squares, sample averages, and isotonic regression.

A random walk rule for phase I clinical trials.

We describe a family of random walk rules for the sequential allocation of dose levels to patients in a dose-response study, or phase I clinical trial. Patients are sequentially assigned the next higher, same, or next lower dose level according to some probability distribution, which may be determined by ethical considerations as well as the patient's response. It is shown that one can choose these probabilities in order to center dose level assignments unimodally around any target quantile of interest.

Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation: analysis of factors associated with infection.

This study analyzed factors associated with acute oropharyngeal herpes simplex virus (HSV) infection in 627 patients who had undergone allogeneic bone marrow transplantation for leukemia, lymphoma, or aplastic anemia. HSV infection developed in 233 (37%) of the patients; all but two were seropositive for HSV before transplant. Sixty-two percent of the seropositive patients had at least one episode of HSV reactivation during the first 100 days after transplant.

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy.

Nine patients with advanced hematological malignancy were entered into a phase I study to determine the maximum tolerated doses of cytosine arabinoside (Ara-C) and cyclophosphamide (CY) combined with a standard dose of total body irradiation (TBI). Ara-C was administered continuously over 36 h and two doses of CY were given at 24-h intervals during Ara-C administration. TBI was given as 2.

Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation.

We conducted a randomized, double-blind comparison of prednisone and placebo (group I) v prednisone and azathioprine (1.5 mg/kg/day) (group II) as early treatment of extensive chronic graft-v-host disease (GVHD). Patients with platelet counts less than 100,000/microL were placed into therapy with prednisone alone (group III).

Early oral changes following bone marrow transplantation.

This study assessed and analyzed the early oral changes following chemoradiotherapy and bone marrow transplantation. The most notable changes involved mucosal color (white and red), atrophy, vascularity, ulceration, increased salivary viscosity and xerostomia, and the patients' subjective complaints of dryness and oral pain. The ventral tongue, buccal and labial mucosa, and marginal gingiva manifested the most notable changes, while the palate was least affected.

Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation.

Patients undergoing allogeneic bone marrow transplantation who are seropositive for cytomegalovirus are vulnerable to serious cytomegalovirus infection, presumably because of reactivation of latent endogenous virus and severe immunosuppression. We administered intravenous acyclovir from 5 days before to 30 days after allogeneic marrow transplantation for hematologic neoplasms in an effort to prevent cytomegalovirus infection and disease in patients seropositive for cytomegalovirus before transplantation. Eighty-six patients seropositive for both cytomegalovirus and herpes simplex virus before transplantation received acyclovir, whereas 65 patients seropositive only for cytomegalovirus served as controls (acyclovir is the standard prophylactic agent against herpes simplex virus in this setting).

Prophylactic use of human leukocyte interferon after allogeneic marrow transplantation.

Study Objective: To determine the efficacy of prophylactic interferon for prevention of cytomegalovirus infection and relapse of leukemia after allogeneic marrow transplantation.

Design: Randomized trial with intermittent interferon administration to day 80 after transplantation.

Setting: Marrow transplantation units of a cancer research center.

Risk factors for airflow obstruction in recipients of bone marrow transplants.

Obstructive lung disease is a complication of bone marrow transplantation. To identify risk factors we analyzed pulmonary function tests of 281 adult patients 1 year after marrow transplantation. The forced expiratory volume at 1 second divided by the forced vital capacity (FEV1/FVC) was used to measure airflow rates.