An Introduction to Practical Sequential Inferences via Single-Arm Binary Response Studies Using the binseqtest R Package

<div><p>We review sequential designs, including group sequential and two-stage designs, for testing or estimating a single binary parameter. We use this simple case to introduce ideas common to many sequential designs, which in this case can be explained without explicitly using stochastic processes. We focus on methods provided by our newly developed R package, binseqtest, which exactly bound the Type I error rate of tests and exactly maintain proper coverage of confidence intervals. Within this framework, we review some allowable practical adaptations of the sequential design. We explore issues such as the following: How should the design be modified if no assessment was made at one of the planned sequential stopping times? How should the parameter be estimated if the study needs to be stopped early? What reasons for stopping early are allowed? How should inferences be made when the study is stopped for crossing the boundary, but later information is collected about responses of subjects that had enrolled before the decision to stop but had not responded by that time? Answers to these questions are demonstrated using basic methods that are available in our binseqtest R package. Supplementary materials for this article are available online.</p></div

Dataset for: A rank test for bivariate event time outcomes when one event is a surrogate

In many clinical settings, improving patient survival is of interest but a practical surrogate, such as time to disease progression, is instead used as a clinical trial's primary endpoint. A time-to-first endpoint (e.g. death or disease progression) is commonly analyzed but may not be adequate to summarize patient outcomes if a subsequent event contains important additional information. We consider a surrogate outcome very generally, as one correlated with the true endpoint of interest. Settings of interest include those where the surrogate indicates a beneficial outcome so that the usual time-to-first endpoint of death or surrogate event is nonsensical. We present a new two-sample test for bivariate, interval-censored time-to-event data, where one endpoint is a surrogate for the second, less frequently observed endpoint of true interest. This test examines whether patient groups have equal clinical severity. If the true endpoint rarely occurs, the proposed test acts like a weighted logrank test on the surrogate; if it occurs for most individuals, then our test acts like a weighted logrank test on the true endpoint. If the surrogate is a useful statistical surrogate, our test can have better power than tests based on the surrogate that naively handle the true endpoint. In settings where the surrogate is not valid (treatment affects the surrogate but not the true endpoint), our test incorporates the information regarding the lack of treatment effect from the observed true endpoints and hence is expected to have a dampened treatment effect compared to tests based on the surrogate alone

Statistical Methods for Standard Membrane-Feeding Assays to Measure Transmission Blocking or Reducing Activity in Malaria

<p>Transmission blocking vaccines for malaria are not designed to directly protect vaccinated people from malaria disease, but to reduce the probability of infecting other people by interfering with the growth of the malaria parasite in mosquitoes. Standard membrane-feeding assays compare the growth of parasites in mosquitoes from a test sample (using antibodies from a vaccinated person) compared to a control sample. There is debate about whether to estimate the transmission reducing activity (TRA) which compares the mean number of parasites between test and control samples, or transmission blocking activity (TBA) which compares the proportion of infected mosquitoes. TBA appears biologically more important since each mosquito with any parasites is potentially infective; however, TBA is less reproducible and may be an overly strict criterion for screening vaccine candidates. Through a statistical model, we show that the TBA estimand depends on μ_<i>c</i>, the mean number of parasites in the control mosquitoes, a parameter not easily experimentally controlled. We develop a standardized TBA estimator based on the model and a given target value for μ_<i>c</i> which has better mean squared error than alternative methods. We discuss types of statistical inference needed for using these assays for vaccine development. Supplementary materials for this article are available online.</p

Heatmap depicting circulating microbial products, acute phase proteins and inflammatory cytokines in CP Ag+ individuals compared to EN, INF and CP Ag− individuals.

<p>Data (and scale) are log10 geometric mean fold change from EN for each of the analytes measured for each of the groups.</p

Correlation between circulating microbial products and inflammatory cytokines in filarial infected individuals.

<p>(A) Plasma levels of LPS were correlated with the levels of IL-1β, IL-6, IL-12 and TNF-α from individuals with active infection [CP Ag+ and INF (<i>n</i> = 108–112)]. (B) Plasma levels of LBP were correlated with the levels of IL-1β, IL-6, IL-12 and TNF-α from individuals with active infection [CP Ag+ and INF (<i>n</i> = 108–112)]. P and r values were calculated using the Spearman Rank correlation test. Data are shown as scatter plots with the circles representing INF and the triangles representing CP Ag+ individuals.</p

Holm's adjusted p-values from Linear Models, No Age Effect, n = sample size.

<p>Holm's adjusted p-values from Linear Models, No Age Effect, n = sample size.</p

Characteristics of the study population.

*<p>CFA values are determined by the Og4C3 ELISA and 32 IU was the threshold of detection in the assay.</p

Fold-change for geometric mean of CP Ag+ group compared to others, with (unadjusted) 95% confidence intervals (CI).

<p>Fold-change for geometric mean of CP Ag+ group compared to others, with (unadjusted) 95% confidence intervals (CI).</p

Filarial lymphedema is associated with elevated levels of acute phase proteins.

<p>Plasma levels of CRP, Haptoglobin, SAA and α-2 macroglobulin from asymptomatic infected [INF] individuals; filarial lymphedema individuals with active infection [CP Ag+]; filarial lymphedema individuals without active infection [CP Ag−] and endemic normal [EN] individuals were measured by ELISA. Data are shown as scatter plots with the bar representing the geometric mean.</p

Filarial lymphedema is associated with elevated levels of inflammatory cytokines.

<p>Plasma levels of IL-1β, IL-6, IL-12 and TNF-α from asymptomatic infected [INF] individuals; filarial lymphedema individuals with active infection [CP Ag+]; filarial lymphedema individuals without active infection [CP Ag−] and endemic normal [EN] individuals were measured by ELISA. Data are shown as scatter plots with the bar representing the geometric mean.</p