The Lasso and the Monkey: Feature Selection, Extraction, and Testing in Repeated Low-Dose Challenge Data

Progression of technology and computational power have led to a new age in data where the number of variables, p, is greater than the number of observations, n. These types of data, commonly called High-Dimensional Low Sample Size (HDLSS) data, are becoming prominent in statistical applications. One such HDLSS application where small samples are unavoidable is in the development and pre-clinical assessment of new drugs, such as in repeated low-dose challenge (RLC) studies. In RLC experiments, animals are assigned to an active or placebo candidate vaccine and then are repeatedly challenged (exposed) with some target pathogen, either until infection or some maximum number of challenges is reached (Nolen et al., 2015). Many times, the number of animals n in an RLC study is small (e.g. ≤ 20) and number of features p is large (e.g. ≥ 100), due to the high cost of each animal and the high number of antibody and functional measure features of interest (Chaudhury et al., 2018; Choi et al., 2015). Penalized regression techniques, like the lasso, are sometimes used in RLC experiments where n is typically small and p is large. However, the performance of such methods is not well established for this experiment setting. The performance of the lasso, elastic net, and a newly proposed discrete survival time penalized regression model is assessed via a simulation study. These methods are also applied to a recent RLC study evaluating a candidate HIV vaccine. All three methods rarely selected true positives regardless of the effect size, number of predictors, or the number of non-zero coefficients, with many models containing only false positives. Thus, penalized regression models should be used cautiously in the RLC setting when n is small and p is large. To improve upon penalized regression in the RCL setting, a recently-developed high-dimensional test known as the direction-projection-permutation (DiProPerm) test is suggested and adapted to the RLC setting. The DiProPerm test was designed specifically for the HDLSS setting and has many alluring qualities. The DiProPerm test is applied to the RLC setting to test whether animals are more likely to become infected early (i.e., before the median infection time) as opposed to late, given a set of antibody and functional measurements. The DiProPerm test has never been implemented in RLC settings as a valid tool for inference until now. Simulation processes revealed the advantages of using the DiProPerm test on RLC data when n is small and p is large. An RLC study evaluating a candidate HIV vaccine is used to demonstrate the DiProPerm test on a real-world dataset. To help disseminate the DiProPerm test to researchers, an R package was created. The diproperm R package can be used to conduct a DiProPerm test, display corresponding plots of interest, and look at the loadings of the binary linear classifier. The functionality of the diproperm package is explained and demonstrated on a real-world data set. The R package is freely available on CRAN and GitHub (https://github.com/allmondrew/diproperm) for anyone to use.Doctor of Public Healt

Estimating HIV Medication Adherence and Persistence: Two Instruments for Clinical and Research Use

Antiretroviral therapy (ART) requires lifelong daily oral therapy. While patient characteristics associated with suboptimal ART adherence and persistence have been described in cohorts of HIV-infected persons, these factors are poor predictors of individual medication taking behaviors. We aimed to create and test instruments for the estimation of future ART adherence and persistence for clinical and research applications. Following formative work, a battery of 148 items broadly related to HIV infection and treatment was developed and administered to 181 HIV-infected patients. ART adherence and persistence were assessed using electronic monitoring for 3 months. Perceived confidence in medication taking and self-reported barriers to adherence were strongest in predicting non-adherence over time. Barriers to adherence (e.g., affordability, scheduling) were the strongest predictors of non-adherence, as well as 3- and 7-day non-persistence. A ten-item battery for prediction of these outcomes (www.med.unc.edu/ncaidstraining/adherence/for-providers) and a 30-item battery reflective of underlying psychological constructs can help identify and study individuals at risk for suboptimal ART adherence and persistence

F17RS SGR No. 2 (Best Wishes Scalise)

A RESOLUTION Conveying Best Wishes to Rep. Steve Scalise on His Recover

Financial Incentives for Adherence to Hepatitis C Virus Clinical Care and Treatment: A Randomized Trial of Two Strategies

Although rates of sustained virologic response (SVR) after hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) surpass 90% in trials and some more “real world” settings, some patients, such as those with substance use disorders, will be challenged to adhere to HCV care

Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design

Quantifying tissue drug concentrations can yield important information during drug development, but complicates pharmacokinetic study design. Mucosal fluids collected by direct aspiration(cervicovaginal fluid; CVF) or swab(rectal fluid; RF) might be used as tissue concentration surrogates, but these relationships are not well characterized

Seasonal variation and an “outbreak” of frog predation by tamarins

We report temporal variation and an “outbreak” of frog predation by moustached tamarins, Saguinus mystax, in north-eastern Peruvian Amazonia. Frog predation rates were generally very low, but strongly increased in October 2015. Other high rates, identified by outlier analyses, were also observed in September–November of other years. Over all study years, predation rates in this 3-month period were significantly higher than those in the remainder of the year, suggesting a seasonal pattern of frog predation by tamarins. Reduced fruit availability or increased frog abundance or a combination of both may be responsible for both the seasonal pattern and the specific “outbreak” of frog predation

A multicenter retrospective study of patients with pulmonary hypertension transitioned from inhaled to oral treprostinil

Oral treprostinil has recently been shown to delay disease progression in patients with pulmonary arterial hypertension in a long-term outcomes study. The potential advantages of an oral formulation have resulted in patients transitioning from inhaled to oral treprostinil. The current study reports a retrospective analysis of patients who transitioned from treatment with inhaled to oral treprostinil. A multicenter retrospective chart review was conducted for 29 patients with pulmonary hypertension that transitioned from inhaled to oral treprostinil. Data were collected from inhaled treprostinil initiation and patients were followed until discontinuation of oral treprostinil or the end of the observation period. Persistence was calculated using Kaplan-Meier estimates. Prior to transition to oral treprostinil, patients had received inhaled treprostinil for a median of 643 (IQR: 322-991) days and 52% of patients were New York Heart Association/World Health Organization Functional Class III. For patients that cross-titrated between formulations, the median time to complete the cross titration was 24 (IQR: 1-57) days. At 16- and 24-weeks post-transition, oral treprostinil persistence was 86 and 76%, respectively. Persistence was 59% at 52 weeks post-transition. Clinical stability for the majority of patients at first follow-up post-transition was suggested based on available New York Heart Association/World Health Organization Functional Classification. Transitions from inhaled to oral treprostinil appeared safe and tolerable in the short-term. Additional prospective studies are needed to fully evaluate the safety and efficacy of transitions from inhaled to oral treprostinil