Statistical Communications in Infectious Diseases

Published by De Gruyter

Volume 9 Issue 1 -

January 2017

Issue of Statistical Communications in Infectious Diseases

Contents
Journal Overview

March 14, 2017

Evaluating Anti-infective Drugs in the Resistant Pathogen Setting: Can We Use External Controls?

Scott R Evans, John Powers

Article number: 20160003

Abstract

Decreased efficacy of antibiotics due to resistant pathogens has created a need for the development of more effective medical interventions. Despite the increasing prevalence of pathogens resistant to one or more drugs, identifying and enrolling participants into clinical trials that evaluate new interventions for the treatment of some diseases can be challenging given the low prevalence of disease in which there are no effective treatments. Thus researchers might be tempted to consider externally-controlled trials that may allow for a reduction of the necessary number of prospectively-identified trial participants, thus easing recruitment burden and resulting in more timely trial completion relative to randomized controlled trials. We discuss advantages and disadvantages in externally controlled trials and review requirements for a valid externally-controlled trial. As ECTs are subject to the bias of observational studies, the criteria for a valid ECT should be carefully evaluated before these designs are implemented. Given considerable variation in study results in the resistant pathogen setting, the lack of information on important patient characteristics that may confound estimates of treatment effects, as well as the improvements in medical practice and evolving antibiotic resistance, the use of ECTs in the resistant pathogen setting, is not recommended. ECTs should be should be limited to specific situations where superiority of the effect of the new intervention is dramatic, the usual course of the disease highly predictable, the endpoints are objective (e. g., all-cause mortality) and the impact of baseline and treatment variables on outcomes is well characterized. Given that the resistant pathogen setting does not satisfy these criteria, we conclude that that randomized clinical trials are needed to evaluate new treatments for resistant pathogens. Innovative approaches to trial design that may ease recruitment burden while evaluating the benefits and harms of new treatments are being developed and utilized.

March 14, 2017

Cross-Sectional HIV Incidence Surveillance: A Benchmarking of Approaches for Estimating the ‘Mean Duration of Recent Infection’

Reshma Kassanjee, Daniela De Angelis, Marian Farah, Debra Hanson, Jan Phillipus Lourens Labuschagne, Oliver Laeyendecker, Stéphane Le Vu, Brian Tom, Rui Wang, Alex Welte

Article number: 20160002

Abstract

The application of biomarkers for ‘recent’ infection in cross-sectional HIV incidence surveillance requires the estimation of critical biomarker characteristics. Various approaches have been employed for using longitudinal data to estimate the Mean Duration of Recent Infection (MDRI) – the average time in the ‘recent’ state. In this systematic benchmarking of MDRI estimation approaches, a simulation platform was used to measure accuracy and precision of over twenty approaches, in thirty scenarios capturing various study designs, subject behaviors and test dynamics that may be encountered in practice. Results highlight that assuming a single continuous sojourn in the ‘recent’ state can produce substantial bias. Simple interpolation provides useful MDRI estimates provided subjects are tested at regular intervals. Regression performs the best – while ‘random effects’ describe the subject-clustering in the data, regression models without random effects proved easy to implement, stable, and of similar accuracy in scenarios considered; robustness to parametric assumptions was improved by regressing ‘recent’/‘non-recent’ classifications rather than continuous biomarker readings. All approaches were vulnerable to incorrect assumptions about subjects’ (unobserved) infection times. Results provided show the relationships between MDRI estimation performance and the number of subjects, inter-visit intervals, missed visits, loss to follow-up, and aspects of biomarker signal and noise.

June 6, 2017

Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials

Peter B Gilbert, Michal Juraska, Allan C. deCamp, Shelly Karuna, Srilatha Edupuganti, Nyaradzo Mgodi, Deborah J Donnell, Carter Bentley, Nirupama Sista, Philip Andrew, Abby Isaacs, Yunda Huang, Lily Zhang, Edmund Capparelli, Nidhi Kochar, Jing Wang, Susan H Eshleman, Kenneth H Mayer, Craig A Magaret, John Hural, James G Kublin, Glenda Gray, David C Montefiori, Margarita M Gomez, David N Burns, Julie McElrath, Julie Ledgerwood, Barney S Graham, John R Mascola, Myron Cohen, Lawrence Corey

Article number: 20160001

Abstract

Background Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. Methods The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. Results Each AMP trial is designed to have 90 % power to detect PE > 0 % if PE is ≥ 60 %. The AMP trials are also designed to identify VRC01 properties (i. e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions. Conclusions The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV-1 prevention.

About this journal

Objective
The mission of Statistical Communications in Infectious Diseases is to serve as the primary vehicle for the communication and education of statistical thinking in infectious disease research and policy.

The infectious diseases community faces many difficult challenges. These include: (1) coping with continuing high-impact diseases such as HIV, malaria, TB, and flu; (2) dealing with infectious disease outbreaks such as Ebola, pandemic avian influenza, or SARS; and (3) preparing for the inevitable emergence of diseases that are unknown or are recognized but will reemerge in a more threatening form (e.g., antibiotic resistant [nightmare] bacteria or superbugs). Research in infectious diseases is also challenged by funding limitations, politics, and ethical dilemmas.

Increasingly complex data is also creating new challenges to the design and analysis of research studies. Enhanced statistical expertise is essential to address these challenges and to develop and evaluate medical and public health responses to potential outbreaks and epidemics.

Statistical Communications in Infectious Diseases (SCID) publishes significant research on the application of statistical ideas to problems arising from studies of infectious diseases. SCID takes a broad perspective on the role of statistics in infectious disease research including application, policy, education and theory. SCID fosters much-needed communication among statisticians on the best approaches to evolving complex infectious disease data, and is a venue for statisticians to enter a dialogue with other scientists and policy makers on the strengths and limitations of policies and methods for design, monitoring, analysis, and reporting of infectious disease research studies.

SCID goes beyond the application of statistical methods to data arising from infectious disease studies or new statistical strategies. SCID serves as a sounding board to discuss policy issues, as well as to accomplish the following goals: (1) engage and raise the quality of the discussions of important issues in the public and scientific press; (2) ensure that optimal scientific tools are utilized in infectious disease research; (3) improve the training and practice of the next generation of professionals involved in infectious diseases research through educational articles; (4) raise the profile of quantitative science in infectious disease research by demonstrating its value in decision making and public health.

Topics

How heavily should the public invest in research or implementation of different prevention modalities?
What is necessary to achieve control of epidemics (for example, do we require a vaccine to control the spread of HIV or what procedures are required to halt the spread of Ebola)?
How can statisticians help with grass roots epidemic control efforts?
How can we optimally evaluate the benefits vs. harms vs. costs of competing interventions?
How can we best characterize the trade-offs between civil liberties and public safety?
How should we adjust the traditionally required level of evidence to address areas of unmet medical need?
How do we revise our traditional approaches to the design, monitoring, analyses, and reporting of infectious disease studies to improve medical practice and public health?

Article formats
Original research articles, book reviews